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Crimean-Congo haemorrhagic fever

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Viral hemorrhagic fever

Viral hemorrhagic fevers ( VHFs ) are a diverse group of animal and human illnesses . VHFs may be caused by five distinct families of RNA viruses : the families Filoviridae , Flaviviridae , Rhabdoviridae , and several member families of the Bunyavirales order such as Arenaviridae , and Hantaviridae . All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in many cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica (a hantavirus ), while others, such as Ebola virus , can cause severe, life-threatening disease.Signs and symptoms of VHFs include (by definition) fever and bleeding: The severity of symptoms varies with the type of virus. The "VHF syndrome" (capillary leak, bleeding diathesis , and circulatory compromise leading to shock) appears in a majority of people with filoviral hemorrhagic fevers (e.g., Ebola and Marburg virus ), Crimean–Congo hemorrhagic fever (CCHF), and the South American hemorrhagic fevers caused by arenaviruses , but only in a small minority of patients with dengue or Rift Valley fever .Five families of RNA viruses have been recognised as being able to cause hemorrhagic fevers. [ citation needed ] The pathogen that caused the cocoliztli epidemics in Mexico of 1545 and 1576 is still unknown, and the 1545 epidemic may have been bacterial rather than viral. Different hemorrhagic fever viruses act on the body in different ways, resulting in different symptoms. In most VHFs, it is likely that several mechanisms contribute to symptoms, including liver damage, disseminated intravascular coagulation (DIC), and bone marrow dysfunction. In DIC, small blood clots form in blood vessels throughout the body, removing platelets necessary for clotting from the bloodstream and reducing clotting ability. DIC is thought to cause bleeding in Rift Valley, Marburg, and Ebola fevers. For filoviral hemorrhagic fevers, there are four general mechanisms of pathogenesis. The first mechanism is dissemination of virus due to suppressed responses by macrophages and dendritic cell (antigen presenting cells). The second mechanism is prevention of antigen specific immune response. The third mechanism is apoptosis of lymphocytes. The fourth mechanism is when infected macrophages interact with toxic cytokines , leading to diapedesis and coagulation deficiency. From the vascular perspective, the virus will infect vascular endothelial cells, leading to the reorganization of the VE-cadherin catenin complex (a protein important in cell adhesion). This reorganization creates intercellular gaps in endothelial cells. The gaps lead to increased endothelial permeability and allow blood to escape from the vascular circulatory system. [ citation needed ] The reasons for variation among patients infected with the same virus are unknown but stem from a complex system of virus-host interactions. Dengue fever becomes more virulent during a second infection by means of antibody-dependent enhancement . After the first infection, macrophages display antibodies on their cell membranes specific to the dengue virus. By attaching to these antibodies, dengue viruses from a second infection are better able to infect the macrophages, thus reducing the immune system's ability to fight off infection. [ citation needed ]Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment capabilities. The findings of laboratory investigation vary somewhat between the viruses but in general, there is a decrease in the total white cell count (particularly the lymphocytes ), a decrease in the platelet count, an increase in the blood serum liver enzymes , and reduced blood clotting ability measured as an increase in both the prothrombin (PT) and activated partial thromboplastin times (PTT). The hematocrit may be elevated. The serum urea and creatine may be raised but this is dependent on the hydration status of the patient. The bleeding time tends to be prolonged. [ citation needed ]With the exception of yellow fever vaccine and Ebola vaccines , vaccines for VHF-associated viruses are generally not available. Post-exposure prophylactic (preventive) ribavirin may be effective for some bunyavirus and arenavirus infections. VHF isolation guidelines dictate that all VHF patients (with the exception of dengue patients) should be cared for using strict contact precautions, including hand hygiene, double gloves, gowns, shoe and leg coverings, and face shield or goggles. Lassa, CCHF, Ebola, and Marburg viruses may be particularly prone to nosocomial (hospital-based) spread. Airborne precautions should be utilized including, at a minimum, a fit-tested , HEPA filter-equipped respirator (such as an N95 mask ), a battery-powered, air-purifying respirator, or a positive pressure supplied air respirator to be worn by personnel coming within 1.8 meter (six feet) of a VHF patient. Groups of patients should be cohorted (sequestered) to a separate building or a ward with an isolated air-handling system. Environmental decontamination is typically accomplished with hypochlorite (e.g. bleach) or phenolic disinfectants . Medical management of VHF patients may require intensive supportive care. Antiviral therapy with intravenous ribavirin may be useful in Bunyaviridae and Arenaviridae infections (specifically Lassa fever, RVF, CCHF, and HFRS due to Old World Hantavirus infection) and can be used only under an experimental protocol as IND approved by the U.S. Food and Drug Administration (FDA). Interferon may be effective in Argentine or Bolivian hemorrhagic fevers (also available only as IND). [ citation needed ]The VHF viruses are spread in a variety of ways. Some may be transmitted to humans through a respiratory route. [ citation needed ] The virus is considered by military medical planners to have a potential for aerosol dissemination, weaponization, or likelihood for confusion with similar agents that might be weaponized.

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Crimean-Congo haemorrhagic fever

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2023 Crimean–Congo hemorrhagic fever outbreak

An outbreak of Crimean–Congo hemorrhagic fever in Namibia , Georgia , Afghanistan , Iraq , and Senegal has been ongoing since 1 January 2023.Crimean–Congo hemorrhagic fever is a viral fever caused by a diverse group of animal and human illnesses. The fever's case fatality rate may still be as high as 40% without prompt treatment. Hemorrhagic fever is a fever to Crimean–Congo areas. The 2023 Crimean–Congo hemorrhagic fever outbreak started in Iraq . Between 1 January and 22 May, 212 cases of CCHF were reported to the WHO. Twenty seven deaths were recorded, of which 13 were in laboratory confirmed cases. The outbreak started on 16 May, and on 23 May the WHO confirmed the first death that occurred on 18 May in Windhoek , Namibia . On 26 May, Georgia reported 8 cases of CCHF that were confirmed. On 27 May, the Afghanistan Health Department reported 10 cases in the province of Balkh .

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Crimean-Congo haemorrhagic fever

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Prevention of viral hemorrhagic fever

Prevention of viral hemorrhagic fever is similar for the different viruses. There are a number of different viral hemorrhagic fevers including Ebola virus disease , Lassa fever , Rift valley fever , Marburg virus disease , Crimean-Congo haemorrhagic fever (CCHF) and yellow fever . Lassa, Ebola, Marburg and CCHF can be spread by direct contact with the body fluids of those infected. Thus the content here covers the prevention of Ebola .The use of standard precautions is recommended with all patients in a healthcare environment. This includes a minimum level of standard precautions for use with all people regardless of their infection status, routine handwashing practices, safe handling and disposal of used needles and syringes, and intensifying standard precautions. It also includes VHF isolation precautions when needed. Limited supplies and resources may prevent a health facility from using all the standard precautions all the time. However, health facilities should establish and maintain a basic, practical level of standard precautions that can be used routinely with patients in their health facility. This requires a source of clean water, routine handwashing before and after any contact with a person who has fever, and safe handling and disposal of sharp instruments and equipment. Washing hands with soap and water eliminates microorganisms from the skin and hands. This provides some protection against transmission of VHF and other diseases. This requires at least cake soap cut into small pieces, soap dishes with openings that allow water to drain away, running water or a bucket kept full with clean water, a bucket for collecting rinse water and a ladle for dipping, if running water is not available, and one-use towels. The handwashing technique that is recommended is to place a piece of soap in the palm of one hand, wash the opposite hand and forearm, rub the surfaces vigorously for at least 10 seconds, move soap to the opposite hand and repeat, use clean water to rinse both hands and then the forearms, dry the hands and forearms with a clean one-use towel, or let rinsed hands and forearms air-dry. Reusable needles and syringes are not recommended. If reusable needles and syringes are used, clean, disinfect and sterilize them before reuse. Needles and syringes used with VHF patients require special care. Cleaning staff should wear two pairs of gloves when handling needles and syringes used with any patient with a known or suspected VHF. In an outbreak situation, several cases occur around the same time. They may be grouped together, and there may be person-to-person transmission. An initial diagnosis of a VHF can be made based on the signs and symptoms of the specific VHF. Suspecting a VHF during a non-outbreak situation in a single case is more difficult. The early symptoms of a VHF include high fever and headache. These are also symptoms for many infections seen at the health facility. Most people who present with fever do not have a VHF. Their fever is more often caused by malaria , typhoid fever , dysentery , severe bacterial infection or other fever-producing illnesses usually seen in the area. The health worker probably will not suspect a VHF until more severe signs develop and the patient does not respond to recommended treatment for other illnesses. However, health workers should be aware of the possibility of VHF in a non-outbreak situation. As soon as a VHF is suspected, VHF isolation precautions should begin. This will help reduce the number of people exposed to the VHF. Isolating the VHF patient will restrict patient access to health facility staff trained to use VHF isolation precautions. Establish a barrier between the VHF patient and uninfected patients, other health facility staff, and visitors. When a VHF case is suspected in the health facility, the following protective clothing should be worn in the isolation area: A scrub suit or inner layer of clothing (an old shirt and trousers brought from home) A pair of thin gloves Rubber boots or overshoes (only if the floor is soiled) A gown or outer layer of clothing (surgical or disposable gown with long sleeves and cuffs) A plastic apron worn over both layers of clothes A second pair of thin or thick gloves. Wearing a second pair of gloves provides an added measure of safety during patient care and when handling contaminated supplies A HEPA-filter (high-efficiency particulate air respirator) or other biosafety mask (or surgical mask if HEPA-filter or other biosafety mask is not available) Cotton head covering Clear eyeglasses or non-fogging goggles When protective clothing is not available or is in short supply, adaptations must be made and used. There are specific recommendation regarding the putting on of protective clothing including: Before entering the changing room, remove jewelry, wallets and other valuables. Remove street clothes and hang them on a hook. Put on the scrub suit or set of old clothes. Enter the changing room. Put on rubber boots. Put on each boot and tuck the trouser leg inside the boot. If overboots are used, tape the top of the boot to the leg with plastic tape. This will help prevent spills from running inside the boots. Put on the first pair of gloves. Look at your hands for cut or broken skin. If the skin is cut or broken, refrain from direct patient contact. Put on one glove at a time. If the scrub suit or set of old clothes has long sleeves, place the edge of each glove under the cuff. When only one pair of gloves is worn, place the edge of the glove over the cuff or gown. If gloves are not available, use plastic bags. Put on one layer now. Attach and close the first layer with tape or elastic bands Put on the outer gown. Pick up the gown from the inside. This is especially important if the gown is being reused Put on the plastic or rubber apron. Put on the second pair of gloves Put on the mask and head cover Put on the protective eyewear. Attach the eyeglasses or goggles behind the head with string or cord to prevent the eyewear from falling off. Introduction Trained oberserver Removing own clothing Examining equipment Hand cleaning Boot covers Inner gloves Coverall N95 respirator surgical hood Outer apron Outer gloves Face shield Verification There are also specific recommendations regarding the removal of protective clothing including: Disinfect the outer pair of gloves, wash the gloved hands in soap and water, dip the gloved hands in 1:100 bleach solution (see below) for one minute Disinfect the apron. Spray or wipe it with 1:100 bleach solution. Disinfect the boots. Use a sprayer containing 1:100 bleach solution to spray boots or hold the foot over a pan or basin and ask another health worker to pour 1:100 bleach solution over the boots or step into a shallow pan containing 1:100 bleach solution and wipe boots on a bleach-drenched cloth Remove the outer pair of gloves Remove the apron and outer gown Disinfect the gloved hands after contact with apron and outer gown. Remove the eyewear, head cover and mask. Remove the boots. Place a towel that has been soaked in 1:100 bleach solution on the floor for health facility staff to stand on when removing boots Remove the inner pair of gloves. Remove inner layer of clothes and dress in street clothes. Wash hands with soap and clean water before leaving the changing roomThere are specific recommendation regarding the putting on of protective clothing including: Before entering the changing room, remove jewelry, wallets and other valuables. Remove street clothes and hang them on a hook. Put on the scrub suit or set of old clothes. Enter the changing room. Put on rubber boots. Put on each boot and tuck the trouser leg inside the boot. If overboots are used, tape the top of the boot to the leg with plastic tape. This will help prevent spills from running inside the boots. Put on the first pair of gloves. Look at your hands for cut or broken skin. If the skin is cut or broken, refrain from direct patient contact. Put on one glove at a time. If the scrub suit or set of old clothes has long sleeves, place the edge of each glove under the cuff. When only one pair of gloves is worn, place the edge of the glove over the cuff or gown. If gloves are not available, use plastic bags. Put on one layer now. Attach and close the first layer with tape or elastic bands Put on the outer gown. Pick up the gown from the inside. This is especially important if the gown is being reused Put on the plastic or rubber apron. Put on the second pair of gloves Put on the mask and head cover Put on the protective eyewear. Attach the eyeglasses or goggles behind the head with string or cord to prevent the eyewear from falling off. Introduction Trained oberserver Removing own clothing Examining equipment Hand cleaning Boot covers Inner gloves Coverall N95 respirator surgical hood Outer apron Outer gloves Face shield VerificationThere are also specific recommendations regarding the removal of protective clothing including: Disinfect the outer pair of gloves, wash the gloved hands in soap and water, dip the gloved hands in 1:100 bleach solution (see below) for one minute Disinfect the apron. Spray or wipe it with 1:100 bleach solution. Disinfect the boots. Use a sprayer containing 1:100 bleach solution to spray boots or hold the foot over a pan or basin and ask another health worker to pour 1:100 bleach solution over the boots or step into a shallow pan containing 1:100 bleach solution and wipe boots on a bleach-drenched cloth Remove the outer pair of gloves Remove the apron and outer gown Disinfect the gloved hands after contact with apron and outer gown. Remove the eyewear, head cover and mask. Remove the boots. Place a towel that has been soaked in 1:100 bleach solution on the floor for health facility staff to stand on when removing boots Remove the inner pair of gloves. Remove inner layer of clothes and dress in street clothes. Wash hands with soap and clean water before leaving the changing roomDisinfection kills almost all bacteria, fungi, viruses, and protozoa. It reduces the number of microorganisms to make equipment and surfaces safer for use. When VHF is suspected in the health facility, all medical, nursing, laboratory and cleaning staff should disinfect: Hands and skin after contact with a VHF patient or infectious body fluids Gloved hands after contact with each VHF patient or after contact with infectious body fluids (when gloves cannot be changed) Thermometers, stethoscopes and other medical instruments after use with each VHF patient Spills of infectious body fluids on the walls and floors Patient excreta and containers contaminated by patient excreta Reusable supplies such as protective clothing and patient bedding Used needles and syringes Two strengths of solution are recommended. 1:10 bleach solution is a strong solution used to disinfect excreta and bodies. It is also used to prepare the 1:100 bleach solution. 1:100 bleach solution is used to disinfect surfaces, medical equipment, patient bedding, reusable protective clothing before it is laundered, rinsing gloves between contact with each patient, rinsing gloves, apron and boots before leaving the patient's room, disinfecting contaminated waste for disposal The dilutions mentioned pertain to a starting concentration of 5% active chlorine , so the 1:10 solution is 0.5% and the 1:100 is 0.05%. These solutions must be prepared new each day as they lose their strength after 24 hours. Two strengths of solution are recommended. 1:10 bleach solution is a strong solution used to disinfect excreta and bodies. It is also used to prepare the 1:100 bleach solution. 1:100 bleach solution is used to disinfect surfaces, medical equipment, patient bedding, reusable protective clothing before it is laundered, rinsing gloves between contact with each patient, rinsing gloves, apron and boots before leaving the patient's room, disinfecting contaminated waste for disposal The dilutions mentioned pertain to a starting concentration of 5% active chlorine , so the 1:10 solution is 0.5% and the 1:100 is 0.05%. These solutions must be prepared new each day as they lose their strength after 24 hours. Direct, unprotected contact during disposal of infectious waste can result in accidental transmission of VHF. For this reason, all contaminated waste produced in the care of the VHF patient must be disposed of safely. All non-reusable items should be destroyed so they cannot be used again. Burning should be carried out at least daily. Liquid waste, including patient excreta, can be disposed of in an isolated latrine or toilet set aside for VHF cases. Burning is the recommended method for disposal of other VHF-contaminated waste. A safe and inexpensive disposal system can be made by using an incinerator or a pit for burning. Use fuel to accelerate the burning and ensure that all waste is completely destroyed. There is risk of transmission in the health facility when a VHF patient dies because the bodies and body fluids of deceased VHF patients remain contagious for several days after death. Family and community members are also at risk if burial practices involve touching and washing the body. Burial should take place as soon as possible after the body is prepared in the health facility. Health facility staff should prepare the body safely and instruct families on what is and is not safe. To prepare the body, protective clothing is recommended per usually with a second pair of thick rubber gloves. The body and the area around it is sprayed with 1:10 bleach solution. The body is placed in a " body bag " (mortuary sack) and it is closed securely. The body bag is sprayed with 1:10 bleach solution. The body is then transported to the burial site as soon as possible. Any person who must touch or carry the body during transport should wear the same protective clothing as is worn in the isolation area. The grave should be at least 2 meters deep. Viewing the body is not possible and the burial ceremony should be limited to family only. The interior of the vehicle where the body was carried should be rinsed with 1:10 bleach solution. Community education and involvement is an important part of the prevention of the spread of VHF.

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Crimean-Congo haemorrhagic fever

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Ebola

Ebola , also known as Ebola virus disease ( EVD ) and Ebola hemorrhagic fever ( EHF ), is a viral hemorrhagic fever in humans and other primates , caused by ebolaviruses . Symptoms typically start anywhere between two days and three weeks after infection. The first symptoms are usually fever , sore throat , muscle pain , and headaches . These are usually followed by vomiting , diarrhoea , rash and decreased liver and kidney function, at which point some people begin to bleed both internally and externally. It kills between 25% and 90% of those infected – about 50% on average. Death is often due to shock from fluid loss , and typically occurs between six and 16 days after the first symptoms appear. Early treatment of symptoms increases the survival rate considerably compared to late start. An Ebola vaccine was approved by the US FDA in December 2019. The virus spreads through direct contact with body fluids , such as blood from infected humans or other animals, or from contact with items that have recently been contaminated with infected body fluids. There have been no documented cases, either in nature or under laboratory conditions, of spread through the air between humans or other primates . After recovering from Ebola, semen or breast milk may continue to carry the virus for anywhere between several weeks to several months. Fruit bats are believed to be the normal carrier in nature ; they are able to spread the virus without being affected by it. The symptoms of Ebola may resemble those of several other diseases, including malaria , cholera , typhoid fever , meningitis and other viral hemorrhagic fevers. Diagnosis is confirmed by testing blood samples for the presence of viral RNA , viral antibodies or the virus itself. Control of outbreaks requires coordinated medical services and community engagement, including rapid detection, contact tracing of those exposed, quick access to laboratory services, care for those infected, and proper disposal of the dead through cremation or burial. Prevention measures involve wearing proper protective clothing and washing hands when in close proximity to patients and while handling potentially infected bushmeat , as well as thoroughly cooking bushmeat. An Ebola vaccine was approved by the US FDA in December 2019. While there is no approved treatment for Ebola as of 2019 [ update ] , two treatments ( atoltivimab/maftivimab/odesivimab and ansuvimab ) are associated with improved outcomes. Supportive efforts also improve outcomes. These include oral rehydration therapy (drinking slightly sweetened and salty water) or giving intravenous fluids , and treating symptoms. In October 2020, atoltivimab/maftivimab/odesivimab (Inmazeb) was approved for medical use in the United States to treat the disease caused by Zaire ebolavirus . Ebola was first identified in 1976, in two simultaneous outbreaks, one in Nzara (a town in South Sudan ) and the other in Yambuku ( the Democratic Republic of the Congo ), a village near the Ebola River , for which the disease was named. Ebola outbreaks occur intermittently in tropical regions of sub-Saharan Africa . Between 1976 and 2012, according to the World Health Organization , there were 24 outbreaks of Ebola resulting in a total of 2,387 cases, and 1,590 deaths . The largest Ebola outbreak to date was an epidemic in West Africa from December 2013 to January 2016, with 28,646 cases and 11,323 deaths. On 29 March 2016, it was declared to no longer be an emergency. Other outbreaks in Africa began in the Democratic Republic of the Congo in May 2017, and 2018. In July 2019, the World Health Organization declared the Congo Ebola outbreak a world health emergency . The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, and usually between 4 and 10 days. However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. Symptoms usually begin with a sudden influenza -like stage characterised by fatigue , fever , weakness , decreased appetite , muscular pain , joint pain , headache, and sore throat. The fever is usually higher than 38.3 °C (101 °F) . This is often followed by nausea, vomiting, diarrhoea , abdominal pain, and sometimes hiccups . The combination of severe vomiting and diarrhoea often leads to severe dehydration . Next, shortness of breath and chest pain may occur, along with swelling , headaches , and confusion . In about half of the cases, the skin may develop a maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. In some cases, internal and external bleeding may occur. This typically begins five to seven days after the first symptoms. All infected people show some decreased blood clotting . Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. This may cause vomiting blood , coughing up of blood , or blood in stool . Bleeding into the skin may create petechiae , purpura , ecchymoses or haematomas (especially around needle injection sites). Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually in the gastrointestinal tract . The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, but in the 2014–15 outbreak in the US it was ~18%, possibly due to improved prevention of disseminated intravascular coagulation . Recovery may begin between seven and 14 days after first symptoms. Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to shock from fluid loss . In general, bleeding often indicates a worse outcome, and blood loss may result in death. People are often in a coma near the end of life. Those who survive often have ongoing muscular and joint pain, liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. Problems with vision may develop. It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. Survivors develop antibodies against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, and usually between 4 and 10 days. However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. Symptoms usually begin with a sudden influenza -like stage characterised by fatigue , fever , weakness , decreased appetite , muscular pain , joint pain , headache, and sore throat. The fever is usually higher than 38.3 °C (101 °F) . This is often followed by nausea, vomiting, diarrhoea , abdominal pain, and sometimes hiccups . The combination of severe vomiting and diarrhoea often leads to severe dehydration . Next, shortness of breath and chest pain may occur, along with swelling , headaches , and confusion . In about half of the cases, the skin may develop a maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. In some cases, internal and external bleeding may occur. This typically begins five to seven days after the first symptoms. All infected people show some decreased blood clotting . Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. This may cause vomiting blood , coughing up of blood , or blood in stool . Bleeding into the skin may create petechiae , purpura , ecchymoses or haematomas (especially around needle injection sites). Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually in the gastrointestinal tract . The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, but in the 2014–15 outbreak in the US it was ~18%, possibly due to improved prevention of disseminated intravascular coagulation . Recovery may begin between seven and 14 days after first symptoms. Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to shock from fluid loss . In general, bleeding often indicates a worse outcome, and blood loss may result in death. People are often in a coma near the end of life. Those who survive often have ongoing muscular and joint pain, liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. Problems with vision may develop. It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. Survivors develop antibodies against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. EVD in humans is caused by four of six viruses of the genus Ebolavirus . The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV) and one simply called Ebola virus (EBOV, formerly Zaire Ebola virus). EBOV, species Zaire ebolavirus , is the most dangerous of the known EVD-causing viruses, and is responsible for the largest number of outbreaks. The fifth and sixth viruses, Reston virus (RESTV) and Bombali virus (BOMV), are not thought to cause disease in humans, but have caused disease in other primates. All five viruses are closely related to marburgviruses . Ebolaviruses contain single-stranded, non-infectious RNA genomes . Ebolavirus genomes contain seven genes including 3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins , DC-SIGN , or integrins , which is followed by fusion of the viral envelope with cellular membranes . The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved. This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid . The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. The viral RNA polymerase , encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs , which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane . Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease. Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen . The WHO states that only people who are very sick are able to spread Ebola disease in saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit. Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. Ebola may be spread through large droplets ; however, this is believed to occur only when a person is very sick. This contamination can happen if a person is splashed with droplets. Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via sexual intercourse . Virus persistence in semen for over a year has been recorded in a national screening programme. Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood. Otherwise, people who have recovered are not infectious. The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low. Usually when someone has symptoms of the disease, they are unable to travel without assistance. Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk. Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. Health-care workers treating people with Ebola are at greatest risk of infection. The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. There has been transmission in hospitals in some African countries that reuse hypodermic needles. Some health-care centres caring for people with the disease do not have running water. In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates , but not from primates to primates. Spread of EBOV by water, or food other than bushmeat, has not been observed. No spread by mosquitos or other insects has been reported. Other possible methods of transmission are being studied. Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as baboons , great apes ( chimpanzees and gorillas ), and duikers (a species of antelope ). Animals may become infected when they eat fruit partially eaten by bats carrying the virus. Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate. Three types of fruit bats ( Hypsignathus monstrosus , Epomops franqueti and Myonycteris torquata ) were found to possibly carry the virus without getting sick. As of 2013 [ update ] , whether other animals are involved in its spread is not known. Plants, arthropods , rodents , and birds have also been considered possible viral reservoirs. Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys ) and one shrew ( Sylvisorex ollula ) collected from the Central African Republic . However, further research efforts have not confirmed rodents as a reservoir. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. Ebolaviruses contain single-stranded, non-infectious RNA genomes . Ebolavirus genomes contain seven genes including 3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins , DC-SIGN , or integrins , which is followed by fusion of the viral envelope with cellular membranes . The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved. This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid . The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. The viral RNA polymerase , encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs , which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane . Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease. Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen . The WHO states that only people who are very sick are able to spread Ebola disease in saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit. Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. Ebola may be spread through large droplets ; however, this is believed to occur only when a person is very sick. This contamination can happen if a person is splashed with droplets. Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via sexual intercourse . Virus persistence in semen for over a year has been recorded in a national screening programme. Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood. Otherwise, people who have recovered are not infectious. The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low. Usually when someone has symptoms of the disease, they are unable to travel without assistance. Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk. Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. Health-care workers treating people with Ebola are at greatest risk of infection. The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. There has been transmission in hospitals in some African countries that reuse hypodermic needles. Some health-care centres caring for people with the disease do not have running water. In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates , but not from primates to primates. Spread of EBOV by water, or food other than bushmeat, has not been observed. No spread by mosquitos or other insects has been reported. Other possible methods of transmission are being studied. Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as baboons , great apes ( chimpanzees and gorillas ), and duikers (a species of antelope ). Animals may become infected when they eat fruit partially eaten by bats carrying the virus. Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate. Three types of fruit bats ( Hypsignathus monstrosus , Epomops franqueti and Myonycteris torquata ) were found to possibly carry the virus without getting sick. As of 2013 [ update ] , whether other animals are involved in its spread is not known. Plants, arthropods , rodents , and birds have also been considered possible viral reservoirs. Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys ) and one shrew ( Sylvisorex ollula ) collected from the Central African Republic . However, further research efforts have not confirmed rodents as a reservoir. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. Like other filoviruses , EBOV replicates very efficiently in many cells , producing large amounts of virus in monocytes , macrophages , dendritic cells and other cells including liver cells , fibroblasts , and adrenal gland cells . Viral replication triggers high levels of inflammatory chemical signals and leads to a septic state . EBOV is thought to infect humans through contact with mucous membranes or skin breaks. After infection, endothelial cells (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as macrophages, monocytes , and dendritic cells are the main targets of attack. Following infection, immune cells carry the virus to nearby lymph nodes where further reproduction of the virus takes place. From there the virus can enter the bloodstream and lymphatic system and spread throughout the body. Macrophages are the first cells infected with the virus, and this infection results in programmed cell death . Other types of white blood cells , such as lymphocytes , also undergo programmed cell death leading to an abnormally low concentration of lymphocytes in the blood. This contributes to the weakened immune response seen in those infected with EBOV. Endothelial cells may be infected within three days after exposure to the virus. The breakdown of endothelial cells leading to blood vessel injury can be attributed to EBOV glycoproteins . This damage occurs due to the synthesis of Ebola virus glycoprotein (GP), which reduces the availability of specific integrins responsible for cell adhesion to the intercellular structure and causes liver damage, leading to improper clotting . The widespread bleeding that occurs in affected people causes swelling and shock due to loss of blood volume . The dysfunctional bleeding and clotting commonly seen in EVD has been attributed to increased activation of the extrinsic pathway of the coagulation cascade due to excessive tissue factor production by macrophages and monocytes. After infection, a secreted glycoprotein , small soluble glycoprotein (sGP or GP) is synthesised. EBOV replication overwhelms protein synthesis of infected cells and the host immune defences. The GP forms a trimeric complex , which tethers the virus to the endothelial cells. The sGP forms a dimeric protein that interferes with the signalling of neutrophils , another type of white blood cell. This enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. [ medical citation needed ] Furthermore, the virus is capable of hijacking cellular metabolism. Studies have shown that Ebola virus-like particles can reprogram metabolism in both vascular and immune cells. Filoviral infection also interferes with proper functioning of the innate immune system . EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha , interferon-beta , and interferon gamma . The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5 ) or outside of the cytosol (such as Toll-like receptor 3 (TLR3) , TLR7 , TLR8 and TLR9 ) recognise infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signalling cascade that leads to the expression of type 1 interferons . The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighbouring cell. Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins STAT1 and STAT2 are activated and move to the cell's nucleus . This triggers the expression of interferon-stimulated genes , which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body. Filoviral infection also interferes with proper functioning of the innate immune system . EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha , interferon-beta , and interferon gamma . The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5 ) or outside of the cytosol (such as Toll-like receptor 3 (TLR3) , TLR7 , TLR8 and TLR9 ) recognise infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signalling cascade that leads to the expression of type 1 interferons . The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighbouring cell. Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins STAT1 and STAT2 are activated and move to the cell's nucleus . This triggers the expression of interferon-stimulated genes , which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body. When EVD is suspected, travel, work history, and exposure to wildlife are important factors with respect to further diagnostic efforts. Possible non-specific laboratory indicators of EVD include a low platelet count ; an initially decreased white blood cell count followed by an increased white blood cell count ; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time , partial thromboplastin time , and bleeding time . Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy . The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture , detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected six to 18 days after symptom onset. During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA. In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever . The symptoms are also similar to those of other viral haemorrhagic fevers such as Marburg virus disease , Crimean–Congo haemorrhagic fever , and Lassa fever . The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever , shigellosis , rickettsial diseases , cholera , sepsis , borreliosis , EHEC enteritis , leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , measles , and viral hepatitis among others. Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukaemia , haemolytic uraemic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary haemorrhagic telangiectasia , Kawasaki disease , and warfarin poisoning. Possible non-specific laboratory indicators of EVD include a low platelet count ; an initially decreased white blood cell count followed by an increased white blood cell count ; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time , partial thromboplastin time , and bleeding time . Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy . The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture , detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected six to 18 days after symptom onset. During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA. In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever . The symptoms are also similar to those of other viral haemorrhagic fevers such as Marburg virus disease , Crimean–Congo haemorrhagic fever , and Lassa fever . The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever , shigellosis , rickettsial diseases , cholera , sepsis , borreliosis , EHEC enteritis , leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , measles , and viral hepatitis among others. Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukaemia , haemolytic uraemic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary haemorrhagic telangiectasia , Kawasaki disease , and warfarin poisoning. An Ebola vaccine , rVSV-ZEBOV , was approved in the United States in December 2019. It appears to be fully effective ten days after being given. It was studied in Guinea between 2014 and 2016. More than 100,000 people have been vaccinated against Ebola as of 2019 [ update ] . The WHO reported that approximately 345,000 people were given the vaccine during the Kivu Ebola epidemic from 2018 to 2020. Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. Quarantine, also known as enforced isolation, is usually effective in decreasing spread. Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. In the United States, the law allows quarantine of those infected with ebolaviruses. Contact tracing is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. An Ebola vaccine , rVSV-ZEBOV , was approved in the United States in December 2019. It appears to be fully effective ten days after being given. It was studied in Guinea between 2014 and 2016. More than 100,000 people have been vaccinated against Ebola as of 2019 [ update ] . The WHO reported that approximately 345,000 people were given the vaccine during the Kivu Ebola epidemic from 2018 to 2020. Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. Quarantine, also known as enforced isolation, is usually effective in decreasing spread. Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. In the United States, the law allows quarantine of those infected with ebolaviruses. Contact tracing is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. As of 2019 [ update ] two treatments ( atoltivimab/maftivimab/odesivimab and ansuvimab ) are associated with improved outcomes. The U.S. Food and Drug Administration (FDA) advises people to be careful of advertisements making unverified or fraudulent claims of benefits supposedly gained from various anti-Ebola products. In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab with an indication for the treatment of infection caused by Zaire ebolavirus . Treatment is primarily supportive in nature. Early supportive care with rehydration and symptomatic treatment improves survival. Rehydration may be via the oral or intravenous route. These measures may include pain management , and treatment for nausea , fever , and anxiety . The World Health Organization (WHO) recommends avoiding aspirin or ibuprofen for pain management, due to the risk of bleeding associated with these medications. Blood products such as packed red blood cells , platelets , or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, though there is no evidence to suggest such treatment helps. Several experimental treatments are being studied . Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. Intensive care is often used in the developed world. This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. Dialysis may be needed for kidney failure , and extracorporeal membrane oxygenation may be used for lung dysfunction. Treatment is primarily supportive in nature. Early supportive care with rehydration and symptomatic treatment improves survival. Rehydration may be via the oral or intravenous route. These measures may include pain management , and treatment for nausea , fever , and anxiety . The World Health Organization (WHO) recommends avoiding aspirin or ibuprofen for pain management, due to the risk of bleeding associated with these medications. Blood products such as packed red blood cells , platelets , or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, though there is no evidence to suggest such treatment helps. Several experimental treatments are being studied . Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. Intensive care is often used in the developed world. This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. Dialysis may be needed for kidney failure , and extracorporeal membrane oxygenation may be used for lung dysfunction. EVD has a risk of death in those infected of between 25% and 90%. As of September 2014 [ update ] , the average risk of death among those infected is 50%. The highest risk of death was 90% in the 2002–2003 Republic of the Congo outbreak. Early admission significantly increases survival rates Death, if it occurs, follows typically six to sixteen days after symptoms appear and is often due to low blood pressure from fluid loss . Early supportive care to prevent dehydration may reduce the risk of death. If an infected person survives, recovery may be quick and complete. However, a large portion of survivors develop post-Ebola virus syndrome after the acute phase of the infection. Prolonged cases are often complicated by the occurrence of long-term problems, such as inflammation of the testicles , joint pains , fatigue, hearing loss, mood and sleep disturbances, muscular pain , abdominal pain, menstrual abnormalities , miscarriages , skin peeling , or hair loss . Inflammation and swelling of the uveal layer of the eye is the most common eye complication in survivors of Ebola virus disease. Eye symptoms, such as light sensitivity , excess tearing , and vision loss have been described. Ebola can stay in some body parts like the eyes, breasts, and testicles after infection. Sexual transmission after recovery has been suspected. If sexual transmission occurs following recovery it is believed to be a rare event. One case of a condition similar to meningitis has been reported many months after recovery, as of October 2015 [ update ] . If an infected person survives, recovery may be quick and complete. However, a large portion of survivors develop post-Ebola virus syndrome after the acute phase of the infection. Prolonged cases are often complicated by the occurrence of long-term problems, such as inflammation of the testicles , joint pains , fatigue, hearing loss, mood and sleep disturbances, muscular pain , abdominal pain, menstrual abnormalities , miscarriages , skin peeling , or hair loss . Inflammation and swelling of the uveal layer of the eye is the most common eye complication in survivors of Ebola virus disease. Eye symptoms, such as light sensitivity , excess tearing , and vision loss have been described. Ebola can stay in some body parts like the eyes, breasts, and testicles after infection. Sexual transmission after recovery has been suspected. If sexual transmission occurs following recovery it is believed to be a rare event. One case of a condition similar to meningitis has been reported many months after recovery, as of October 2015 [ update ] . The disease typically occurs in outbreaks in tropical regions of Sub-Saharan Africa . From 1976 (when it was first identified) through 2013, the WHO reported 2,387 confirmed cases with 1,590 overall fatalities. The largest outbreak to date was the Ebola virus epidemic in West Africa , which caused a large number of deaths in Guinea , Sierra Leone , and Liberia . The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. In 2000, Uganda had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a genus Ebolavirus outbreak to date. In 2004, a Russian scientist died from Ebola after sticking herself with an infected needle. Between April and August 2007, a fever epidemic in a four-village region of the DRC was confirmed in September to have been cases of Ebola. Many people who attended the recent funeral of a local village chief died. The 2007 outbreak eventually infected 264 individuals and killed 187. On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of genus Ebolavirus , which was tentatively named Bundibugyo. The WHO reported 149 cases of this new strain and 37 of those led to deaths. The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant in the eastern region. Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana. In 2014, an outbreak occurred in the DRC. Genome-sequencing showed that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak , but was the same EBOV species, the Zaire species. It began in August 2014, and was declared over in November with 66 cases and 49 deaths. This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire . In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea , a West African nation. Researchers traced the outbreak to a one-year-old child who died in December 2013. The disease rapidly spread to the neighbouring countries of Liberia and Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital, Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long." Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases. It caused significant mortality, with a considerable case fatality rate . [note 1] By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. As of 8 May 2016 [ update ] , 28,646 suspected cases and 11,323 deaths were reported; however, the WHO said that these numbers may be underestimated. Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. A new case was detected in Sierra Leone on 14 January 2016. However, the outbreak was declared no longer an emergency on 29 March 2016. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the Bikoro , Iboko, and Wangata areas in Equateur province, including in the large city of Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. On 13 May 2018, WHO Director-General Tedros Adhanom Ghebreyesus visited Bikoro. Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as epidemiologists and officials trying to assess the outbreak and containment efforts. The 2018 outbreak in the DRC was declared over on 24 July 2018. On 1 August 2018, the world's 10th Ebola outbreak was declared in North Kivu province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. As of 4 June 2019 [ update ] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. In June 2019, two people died of Ebola in neighbouring Uganda . In July 2019, an infected man travelled to Goma , home to more than two million people. One week later, on 17 July 2019, the WHO declared the Ebola outbreak a global health emergency , the fifth time such a declaration has been made by the organisation. A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. On 25 June 2020, the second biggest EVD outbreak ever was declared over. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. The 11th EVD outbreak was officially declared over on 19 November 2020. By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths. On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 23 April 2022, a case of Ebola was confirmed in the DRC in the Equateur province. The case was a 31-year-old man whose symptoms began on 5 April, but did not seek treatment for over a week. On 21 April, he was admitted to an Ebola treatment centre and died later that day. By 24 May 2022, there were 5 recorded deaths in the DRC. On 15 August, the fifth case was buried, and the outbreak was declared over, 42 days after, on 4 July 2022. In September 2022, Uganda reported 7 cases infected with the Ebola Sudan strain , but by mid-October the count had increased to 63. In November 2022, the outbreak in Uganda continued - still without a vaccine. On 10 January 2023, the outbreak was considered over after no new cases had been reported for 42 days; the outbreak killed nearly 80 people. The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. In 2000, Uganda had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a genus Ebolavirus outbreak to date. In 2004, a Russian scientist died from Ebola after sticking herself with an infected needle. Between April and August 2007, a fever epidemic in a four-village region of the DRC was confirmed in September to have been cases of Ebola. Many people who attended the recent funeral of a local village chief died. The 2007 outbreak eventually infected 264 individuals and killed 187. On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of genus Ebolavirus , which was tentatively named Bundibugyo. The WHO reported 149 cases of this new strain and 37 of those led to deaths. The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant in the eastern region. Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana. In 2014, an outbreak occurred in the DRC. Genome-sequencing showed that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak , but was the same EBOV species, the Zaire species. It began in August 2014, and was declared over in November with 66 cases and 49 deaths. This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire . In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea , a West African nation. Researchers traced the outbreak to a one-year-old child who died in December 2013. The disease rapidly spread to the neighbouring countries of Liberia and Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital, Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long." Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases. It caused significant mortality, with a considerable case fatality rate . [note 1] By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. As of 8 May 2016 [ update ] , 28,646 suspected cases and 11,323 deaths were reported; however, the WHO said that these numbers may be underestimated. Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. A new case was detected in Sierra Leone on 14 January 2016. However, the outbreak was declared no longer an emergency on 29 March 2016. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the Bikoro , Iboko, and Wangata areas in Equateur province, including in the large city of Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. On 13 May 2018, WHO Director-General Tedros Adhanom Ghebreyesus visited Bikoro. Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as epidemiologists and officials trying to assess the outbreak and containment efforts. The 2018 outbreak in the DRC was declared over on 24 July 2018. On 1 August 2018, the world's 10th Ebola outbreak was declared in North Kivu province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. As of 4 June 2019 [ update ] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. In June 2019, two people died of Ebola in neighbouring Uganda . In July 2019, an infected man travelled to Goma , home to more than two million people. One week later, on 17 July 2019, the WHO declared the Ebola outbreak a global health emergency , the fifth time such a declaration has been made by the organisation. A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. On 25 June 2020, the second biggest EVD outbreak ever was declared over. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. The 11th EVD outbreak was officially declared over on 19 November 2020. By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths.On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 23 April 2022, a case of Ebola was confirmed in the DRC in the Equateur province. The case was a 31-year-old man whose symptoms began on 5 April, but did not seek treatment for over a week. On 21 April, he was admitted to an Ebola treatment centre and died later that day. By 24 May 2022, there were 5 recorded deaths in the DRC. On 15 August, the fifth case was buried, and the outbreak was declared over, 42 days after, on 4 July 2022. In September 2022, Uganda reported 7 cases infected with the Ebola Sudan strain , but by mid-October the count had increased to 63. In November 2022, the outbreak in Uganda continued - still without a vaccine. On 10 January 2023, the outbreak was considered over after no new cases had been reported for 42 days; the outbreak killed nearly 80 people. Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponised for use in biological warfare , and was investigated by Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air. Fake emails pretending to be Ebola information from the WHO or the Mexican government have, in 2014, been misused to spread computer malware. The BBC reported in 2015 that "North Korean state media has suggested the disease was created by the U.S. military as a biological weapon." Richard Preston 's 1995 best-selling book, The Hot Zone , dramatised the Ebola outbreak in Reston, Virginia. William Close 's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire. Tom Clancy 's 1996 novel, Executive Orders , involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka ). As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease. Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponised for use in biological warfare , and was investigated by Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air. Fake emails pretending to be Ebola information from the WHO or the Mexican government have, in 2014, been misused to spread computer malware. The BBC reported in 2015 that "North Korean state media has suggested the disease was created by the U.S. military as a biological weapon." Richard Preston 's 1995 best-selling book, The Hot Zone , dramatised the Ebola outbreak in Reston, Virginia. William Close 's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire. Tom Clancy 's 1996 novel, Executive Orders , involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka ). As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease. Ebola has a high mortality rate among primates. Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas. Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in the 420 km 2 Lossi Sanctuary between 2002 and 2003. Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not. Recovered gorilla carcasses have contained multiple Ebola virus strains, suggesting multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting that transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoirs and animal populations. In 2012, it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus nine percent of those farther away. The authors concluded that there were "potential implications for preventing and controlling human outbreaks." In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia , had an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian haemorrhagic fever virus (SHFV) and occurred amongst a shipment of crab-eating macaque monkeys imported from the Philippines. Hazelton's veterinary pathologist in Reston sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland , where an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV. An electron microscopist from USAMRIID discovered filoviruses similar in appearance, in crystalloid aggregates and as single filaments with a shepherd's hook, to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit. A US Army team headquartered at USAMRIID euthanised the surviving monkeys, and brought all the dead monkeys to Fort Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions. Blood samples were taken from 178 animal handlers during the incident. Of those, six animal handlers eventually seroconverted , including one who had cut himself with a bloody scalpel. Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans. The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident. Reston virus (RESTV) can be transmitted to pigs. Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy, where the virus had infected pigs. According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus . Pigs that have been infected with RESTV tend to show symptoms of the disease. Ebola has a high mortality rate among primates. Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas. Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in the 420 km 2 Lossi Sanctuary between 2002 and 2003. Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not. Recovered gorilla carcasses have contained multiple Ebola virus strains, suggesting multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting that transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoirs and animal populations. In 2012, it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus nine percent of those farther away. The authors concluded that there were "potential implications for preventing and controlling human outbreaks."In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia , had an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian haemorrhagic fever virus (SHFV) and occurred amongst a shipment of crab-eating macaque monkeys imported from the Philippines. Hazelton's veterinary pathologist in Reston sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland , where an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV. An electron microscopist from USAMRIID discovered filoviruses similar in appearance, in crystalloid aggregates and as single filaments with a shepherd's hook, to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit. A US Army team headquartered at USAMRIID euthanised the surviving monkeys, and brought all the dead monkeys to Fort Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions. Blood samples were taken from 178 animal handlers during the incident. Of those, six animal handlers eventually seroconverted , including one who had cut himself with a bloody scalpel. Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans. The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident. Reston virus (RESTV) can be transmitted to pigs. Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy, where the virus had infected pigs. According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus . Pigs that have been infected with RESTV tend to show symptoms of the disease. As of July 2015 [ update ] , no medication has been proven safe and effective for treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014, and early 2015, but some were abandoned due to lack of efficacy or lack of people to study. As of August 2019 [ update ] , two experimental treatments known as atoltivimab/maftivimab/odesivimab and ansuvimab were found to be 90% effective. The diagnostic tests currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. On 29 November 2014, a new 15-minute Ebola test was reported that if successful, "not only gives patients a better chance of survival, but it prevents transmission of the virus to other people." The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. On 29 December 2014, the U.S. Food and Drug Administration (FDA) approved the LightMix Ebola Zaire rRT-PCR test for patients with symptoms of Ebola. Animal models and in particular non-human primates are being used to study different aspects of Ebola virus disease. Developments in organ-on-a-chip technology have led to a chip-based model for Ebola haemorrhagic syndrome. As of July 2015 [ update ] , no medication has been proven safe and effective for treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014, and early 2015, but some were abandoned due to lack of efficacy or lack of people to study. As of August 2019 [ update ] , two experimental treatments known as atoltivimab/maftivimab/odesivimab and ansuvimab were found to be 90% effective. The diagnostic tests currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. On 29 November 2014, a new 15-minute Ebola test was reported that if successful, "not only gives patients a better chance of survival, but it prevents transmission of the virus to other people." The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. On 29 December 2014, the U.S. Food and Drug Administration (FDA) approved the LightMix Ebola Zaire rRT-PCR test for patients with symptoms of Ebola. Animal models and in particular non-human primates are being used to study different aspects of Ebola virus disease. Developments in organ-on-a-chip technology have led to a chip-based model for Ebola haemorrhagic syndrome.

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Crimean-Congo haemorrhagic fever

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Pandemic

A pandemic ( / p æ n ˈ d ɛ m ɪ k / pan-DEM-ik ) is an epidemic of an infectious disease that has spread across a large region, for instance multiple continents or worldwide, affecting a substantial number of individuals. Widespread endemic diseases with a stable number of infected individuals such as recurrences of seasonal influenza are generally excluded as they occur simultaneously in large regions of the globe rather than being spread worldwide. Throughout human history , there have been a number of pandemics of diseases such as smallpox . The Black Death , caused by the Plague , wiped out up to half of the population of Europe in the 14th century. The term pandemic had not been used then, but was used for later epidemics, including the 1918 H1N1 influenza A pandemic—more commonly known as the Spanish flu —which is the deadliest pandemic in history . The most recent pandemics include the HIV/AIDS pandemic , [lower-alpha 1] the 2009 swine flu pandemic and the COVID-19 pandemic . Almost all these diseases still circulate among humans though their impact now is often far less. In response to the COVID-19 pandemic, 194 member states of the World Health Organization began negotiations on an International Treaty on Pandemic Prevention, Preparedness and Response , with a requirement to submit a draft of this treaty to the 77th World Health Assembly during its 2024 convention. A medical dictionary definition of pandemic is " an epidemic occurring on a scale that crosses international boundaries, usually affecting people on a worldwide scale ". A disease or condition is not a pandemic merely because it is widespread or kills many people; it must also be infectious. For instance, cancer is responsible for many deaths but is not considered a pandemic because the disease is not contagious —i.e. easily transmissible—and not even simply infectious . This definition differs from colloquial usage in that it encompasses outbreaks of relatively mild diseases. The World Health Organization (WHO) has a category of Public Health Emergency of International Concern , defined as " an extraordinary event which is determined to constitute a public health risk to other States through the international spread of disease and to potentially require a coordinated international response ". There is a rigorous process underlying this categorization and a clearly defined trajectory of responses. A WHO-sponsored international body, tasked with preparing an international agreement on pandemic prevention, preparedness and response has defined a pandemic as " the global spread of a pathogen or variant that infects human populations with limited or no immunity through sustained and high transmissibility from person to person, overwhelming health systems with severe morbidity and high mortality, and causing social and economic disruptions, all of which require effective national and global collaboration and coordination for its control ". The word comes from the Greek παν- pan- meaning "all", or "every" and δῆμος demos "people". A common early characteristic of a pandemic is a rapid, sometimes exponential , growth in the number of infections, coupled with a widening geographical spread. WHO utilises different criteria to declare a Public Health Emergency of International Concern (PHEIC), its nearest equivalent to the term pandemic. The potential consequences of an incident are considered, rather than its current status. For example, polio was declared a PHEIC in 2014 even though only 482 cases were reported globally in the previous year; this was justified by concerns that polio might break out of its endemic areas and again become a significant health threat globally. The PHEIC status of polio is reviewed regularly and is ongoing, despite the small number of cases annually. [lower-alpha 2] The end of a pandemic is more difficult to delineate. Generally, past epidemics & pandemics have faded out as the diseases become accepted into people's daily lives and routines, becoming endemic . The transition from pandemic to endemic may be defined based on: - a high proportion of the global population having immunity (through either natural infection or vaccination) fewer deaths health systems step down from emergency status perceived personal risk is lessened restrictive measures such as travel restrictions removed less coverage in public media. An endemic disease is always present in a population, but at a relatively low and predictable level. There may be periodic spikes of infections or seasonality, (e.g. influenza ) but generally the burden on health systems is manageable. A common early characteristic of a pandemic is a rapid, sometimes exponential , growth in the number of infections, coupled with a widening geographical spread. WHO utilises different criteria to declare a Public Health Emergency of International Concern (PHEIC), its nearest equivalent to the term pandemic. The potential consequences of an incident are considered, rather than its current status. For example, polio was declared a PHEIC in 2014 even though only 482 cases were reported globally in the previous year; this was justified by concerns that polio might break out of its endemic areas and again become a significant health threat globally. The PHEIC status of polio is reviewed regularly and is ongoing, despite the small number of cases annually. [lower-alpha 2] The end of a pandemic is more difficult to delineate. Generally, past epidemics & pandemics have faded out as the diseases become accepted into people's daily lives and routines, becoming endemic . The transition from pandemic to endemic may be defined based on: - a high proportion of the global population having immunity (through either natural infection or vaccination) fewer deaths health systems step down from emergency status perceived personal risk is lessened restrictive measures such as travel restrictions removed less coverage in public media. An endemic disease is always present in a population, but at a relatively low and predictable level. There may be periodic spikes of infections or seasonality, (e.g. influenza ) but generally the burden on health systems is manageable. Pandemic prevention comprises activities such as anticipatory research and development of therapies and vaccines, as well as monitoring for pathogens and disease outbreaks which may have pandemic potential. Routine vaccination programs are a type of prevention strategy, holding back diseases such as influenza and polio which have caused pandemics in the past, and could do so again if not controlled. Prevention overlaps with preparedness which aims to curtail an outbreak and prevent it getting out of control - it involves strategic planning, data collection and modelling to measure the spread, stockpiling of therapies, vaccines, and medical equipment, as well as public health awareness campaigning. By definition, a pandemic involves many countries so international cooperation, data sharing, and collaboration are essential; as is universal access to tests and therapies. Collaboration - In response to the COVID-19 pandemic, WHO established a Pandemic Hub in September 2021 in Berlin, aiming to address weaknesses around the world in how countries detect, monitor and manage public health threats. The Hub's initiatives include using artificial intelligence to analyse more than 35,000 data feeds for indications of emerging health threats, as well as improving facilities and coordination between academic institutions and WHO member countries. Detection - In May 2023, WHO launched the International Pathogen Surveillance Network (IPSN) (hosted by the Pandemic Hub) aiming to detect and respond to disease threats before they become epidemics and pandemics, and to optimize routine disease surveillance. The network provides a platform to connect countries, improving systems for collecting and analysing samples of potentially harmful pathogens . Therapies and Vaccines - The Coalition for Epidemic Preparedness Innovations (CEPI) is developing a program to condense new vaccine development timelines to 100 days, a third of the time it took to develop a COVID-19 vaccine. CEPI aims to reduce global epidemic and pandemic risk by developing vaccines against known pathogens as well as enabling rapid response to Disease X . In the US, the National Institute of Allergy and Infectious Diseases (NIAID) has developed a Pandemic Preparedness Plan which focuses on identifying viruses of concern and developing diagnostics and therapies (including prototype vaccines) to combat them. Modeling is important to inform policy decisions. It helps to predict the burden of disease on healthcare facilities, the effectiveness of control measures, projected geographical spread, and timing and extent of future pandemic waves. Public Awareness involves disseminating reliable information, ensuring consistency on message, transparency, and steps to discredit misinformation . Stockpiling involves maintaining strategic stockpiles of emergency supplies such as personal protective equipment, drugs and vaccines, and equipment such as respirators. Many of these items have limited shelf life , so they require stock rotation even though they may be rarely used. The COVID-19 pandemic highlighted a number of ethical and political issues which must be considered during a pandemic. These included decisions about who should be prioritised for treatment while resources are scarce; whether or not to make vaccination compulsory; the timing and extent of constraints on individual liberty, how to sanction individuals who do not comply with emergency regulations, and the extent of international collaboration and resource sharing. The COVID-19 pandemic highlighted a number of ethical and political issues which must be considered during a pandemic. These included decisions about who should be prioritised for treatment while resources are scarce; whether or not to make vaccination compulsory; the timing and extent of constraints on individual liberty, how to sanction individuals who do not comply with emergency regulations, and the extent of international collaboration and resource sharing. The basic strategies in the control of an outbreak are containment and mitigation . Containment may be undertaken in the early stages of the outbreak, including contact tracing and isolating infected individuals to stop the disease from spreading to the rest of the population, other public health interventions on infection control, and therapeutic countermeasures such as vaccinations which may be effective if available. When it becomes apparent that it is no longer possible to contain the spread of the disease, management will then move on to the mitigation stage, in which measures are taken to slow the spread of the disease and mitigate its effects on society and the healthcare system. In reality, containment and mitigation measures may be undertaken simultaneously. A key part of managing an infectious disease outbreak is trying to decrease the epidemic peak, known as " flattening the curve ". This helps decrease the risk of health services being overwhelmed and provides more time for a vaccine and treatment to be developed. A broad group of non-pharmaceutical interventions may be taken to manage the outbreak. In a flu pandemic, these actions may include personal preventive measures such as hand hygiene, wearing face-masks, and self-quarantine; community measures aimed at social distancing such as closing schools and canceling mass gatherings; community engagement to encourage acceptance and participation in such interventions; and environmental measures such as cleaning of surfaces. Another strategy, suppression , requires more extreme long-term non-pharmaceutical interventions to reverse the pandemic by reducing the basic reproduction number to less than 1. The suppression strategy, which includes stringent population-wide social distancing, home isolation of cases, and household quarantine, was undertaken by China during the COVID-19 pandemic where entire cities were placed under lockdown; such a strategy may carry with it considerable social and economic costs. For a novel influenza virus , WHO previously applied a six-stage classification to delineate the process by which the virus moves from the first few infections in humans through to a pandemic. Starting with phase 1 (infections identified in animals only), it moves through phases of increasing infection and spread to phase 6 (pandemic). In February 2020, a WHO spokesperson clarified that the system is no longer in use. In 2014, the United States Centers for Disease Control and Prevention (CDC) introduced a framework for characterising the progress of an influenza pandemic titled the Pandemic Intervals Framework . The six intervals of the framework are as follows: investigation of cases of novel influenza, recognition of increased potential for ongoing transmission, initiation of a pandemic wave, acceleration of a pandemic wave, deceleration of a pandemic wave, and preparation for future pandemic waves. At the same time, the CDC adopted the Pandemic Severity Assessment Framework (PSAF) to assess the severity of influenza pandemics. The PSAF rates the severity of an influenza outbreak on two dimensions: clinical severity of illness in infected persons; and the transmissibility of the infection in the population. This tool was not applied during the COVID-19 pandemic. For a novel influenza virus , WHO previously applied a six-stage classification to delineate the process by which the virus moves from the first few infections in humans through to a pandemic. Starting with phase 1 (infections identified in animals only), it moves through phases of increasing infection and spread to phase 6 (pandemic). In February 2020, a WHO spokesperson clarified that the system is no longer in use. In 2014, the United States Centers for Disease Control and Prevention (CDC) introduced a framework for characterising the progress of an influenza pandemic titled the Pandemic Intervals Framework . The six intervals of the framework are as follows: investigation of cases of novel influenza, recognition of increased potential for ongoing transmission, initiation of a pandemic wave, acceleration of a pandemic wave, deceleration of a pandemic wave, and preparation for future pandemic waves. At the same time, the CDC adopted the Pandemic Severity Assessment Framework (PSAF) to assess the severity of influenza pandemics. The PSAF rates the severity of an influenza outbreak on two dimensions: clinical severity of illness in infected persons; and the transmissibility of the infection in the population. This tool was not applied during the COVID-19 pandemic. SARS-CoV-2 , a new strain of coronavirus , was first detected in the city of Wuhan, Hubei Province , China, in December 2019. The outbreak was characterized as a Public Health Emergency of International Concern (PHEIC) between January 2020 and May 2023 by WHO. The number of people infected with COVID-19 has reached more than 767 million worldwide, with a death toll of 6.9 million. [lower-alpha 3] It is considered likely that the virus will eventually become endemic and, like the common cold, cause less severe disease for most people. HIV/AIDS was first identified as a disease in 1981, and is an ongoing worldwide public health issue. Since then, HIV/AIDS has killed an estimated 40 million people with a further 630,000 deaths annually; 39 million people are currently living with HIV infection. [lower-alpha 4] HIV has a zoonotic origin, having originated in nonhuman primates in Central Africa and transferred to humans in the early 20th century. The most frequent mode of transmission of HIV is through sexual contact with an infected person. There may be a short period of mild, nonspecific symptoms followed by an asymptomatic (but nevertheless infectious) stage called clinical latency - without treatment, this stage can last between 3 and 20 years. The only way to detect infection is by means of a HIV test. There is no vaccine to prevent HIV infection, but the disease can be held in check by means of antiretroviral therapy . Historical accounts of epidemics are often vague or contradictory in describing how victims were affected. A rash accompanied by a fever might be smallpox, measles, scarlet fever, or varicella , and it is possible that epidemics overlapped, with multiple infections striking the same population at once. It is often impossible to know the exact causes of mortality, although ancient DNA studies can sometimes detect residues of certain pathogens. It is assumed that, prior to the neolithic revolution around 10,000 BC, disease outbreaks were limited to a single family or clan, and did not spread widely before dying out. The domestication of animals increased human-animal contact, increasing the possibility of zoonotic infections. The advent of agriculture, and trade between settled groups, made it possible for pathogens to spread widely. As population increased, contact between groups became more frequent. A history of epidemics maintained by the Chinese Empire from 243 B.C. to 1911 A.C. shows an approximate correlation between the frequency of epidemics and the growth of the population. Here is an incomplete list of known epidemics which spread widely enough to merit the title "pandemic". Beginning from the Middle Ages, encounters between European settlers and native populations in the rest of the world often introduced epidemics of extraordinary virulence. Settlers introduced novel diseases which were endemic in Europe, such as smallpox , measles , pertussis .and influenza , to which the indigenous peoples had no immunity. The Europeans infected with such diseases typically carried them in a dormant state , were actively infected but asymptomatic , or had only mild symptoms. Smallpox was the most destructive disease that was brought by Europeans to the Native Americans, both in terms of morbidity and mortality. The first well-documented smallpox epidemic in the Americas began in Hispaniola in late 1518 and soon spread to Mexico. Estimates of mortality range from one-quarter to one-half of the population of central Mexico. It is estimated that over the 100 years after European arrival in 1492, the indigenous population of the Americas dropped from 60 million to only 6 million, due to a combination of disease, war, and famine. The majority these deaths are attributed to successive waves of introduced diseases such as smallpox, measles, and typhoid fever. In Australia , smallpox was introduced by European settlers in 1789 devastating the Australian Aboriginal population, killing an estimated 50% of those infected with the disease during the first decades of colonisation. In the early 1800s, measles, smallpox and intertribal warfare killed an estimated 20,000 New Zealand Māori . In 1848–49, as many as 40,000 out of 150,000 Hawaiians are estimated to have died of measles , whooping cough and influenza . Measles killed more than 40,000 Fijians , approximately one-third of the population, in 1875, and in the early 19th century devastated the Great Andamanese population. In Hokkaido , an epidemic of smallpox introduced by Japanese settlers is estimated to have killed 34% of the native Ainu population in 1845. SARS-CoV-2 , a new strain of coronavirus , was first detected in the city of Wuhan, Hubei Province , China, in December 2019. The outbreak was characterized as a Public Health Emergency of International Concern (PHEIC) between January 2020 and May 2023 by WHO. The number of people infected with COVID-19 has reached more than 767 million worldwide, with a death toll of 6.9 million. [lower-alpha 3] It is considered likely that the virus will eventually become endemic and, like the common cold, cause less severe disease for most people. HIV/AIDS was first identified as a disease in 1981, and is an ongoing worldwide public health issue. Since then, HIV/AIDS has killed an estimated 40 million people with a further 630,000 deaths annually; 39 million people are currently living with HIV infection. [lower-alpha 4] HIV has a zoonotic origin, having originated in nonhuman primates in Central Africa and transferred to humans in the early 20th century. The most frequent mode of transmission of HIV is through sexual contact with an infected person. There may be a short period of mild, nonspecific symptoms followed by an asymptomatic (but nevertheless infectious) stage called clinical latency - without treatment, this stage can last between 3 and 20 years. The only way to detect infection is by means of a HIV test. There is no vaccine to prevent HIV infection, but the disease can be held in check by means of antiretroviral therapy . SARS-CoV-2 , a new strain of coronavirus , was first detected in the city of Wuhan, Hubei Province , China, in December 2019. The outbreak was characterized as a Public Health Emergency of International Concern (PHEIC) between January 2020 and May 2023 by WHO. The number of people infected with COVID-19 has reached more than 767 million worldwide, with a death toll of 6.9 million. [lower-alpha 3] It is considered likely that the virus will eventually become endemic and, like the common cold, cause less severe disease for most people. HIV/AIDS was first identified as a disease in 1981, and is an ongoing worldwide public health issue. Since then, HIV/AIDS has killed an estimated 40 million people with a further 630,000 deaths annually; 39 million people are currently living with HIV infection. [lower-alpha 4] HIV has a zoonotic origin, having originated in nonhuman primates in Central Africa and transferred to humans in the early 20th century. The most frequent mode of transmission of HIV is through sexual contact with an infected person. There may be a short period of mild, nonspecific symptoms followed by an asymptomatic (but nevertheless infectious) stage called clinical latency - without treatment, this stage can last between 3 and 20 years. The only way to detect infection is by means of a HIV test. There is no vaccine to prevent HIV infection, but the disease can be held in check by means of antiretroviral therapy . Historical accounts of epidemics are often vague or contradictory in describing how victims were affected. A rash accompanied by a fever might be smallpox, measles, scarlet fever, or varicella , and it is possible that epidemics overlapped, with multiple infections striking the same population at once. It is often impossible to know the exact causes of mortality, although ancient DNA studies can sometimes detect residues of certain pathogens. It is assumed that, prior to the neolithic revolution around 10,000 BC, disease outbreaks were limited to a single family or clan, and did not spread widely before dying out. The domestication of animals increased human-animal contact, increasing the possibility of zoonotic infections. The advent of agriculture, and trade between settled groups, made it possible for pathogens to spread widely. As population increased, contact between groups became more frequent. A history of epidemics maintained by the Chinese Empire from 243 B.C. to 1911 A.C. shows an approximate correlation between the frequency of epidemics and the growth of the population. Here is an incomplete list of known epidemics which spread widely enough to merit the title "pandemic".Beginning from the Middle Ages, encounters between European settlers and native populations in the rest of the world often introduced epidemics of extraordinary virulence. Settlers introduced novel diseases which were endemic in Europe, such as smallpox , measles , pertussis .and influenza , to which the indigenous peoples had no immunity. The Europeans infected with such diseases typically carried them in a dormant state , were actively infected but asymptomatic , or had only mild symptoms. Smallpox was the most destructive disease that was brought by Europeans to the Native Americans, both in terms of morbidity and mortality. The first well-documented smallpox epidemic in the Americas began in Hispaniola in late 1518 and soon spread to Mexico. Estimates of mortality range from one-quarter to one-half of the population of central Mexico. It is estimated that over the 100 years after European arrival in 1492, the indigenous population of the Americas dropped from 60 million to only 6 million, due to a combination of disease, war, and famine. The majority these deaths are attributed to successive waves of introduced diseases such as smallpox, measles, and typhoid fever. In Australia , smallpox was introduced by European settlers in 1789 devastating the Australian Aboriginal population, killing an estimated 50% of those infected with the disease during the first decades of colonisation. In the early 1800s, measles, smallpox and intertribal warfare killed an estimated 20,000 New Zealand Māori . In 1848–49, as many as 40,000 out of 150,000 Hawaiians are estimated to have died of measles , whooping cough and influenza . Measles killed more than 40,000 Fijians , approximately one-third of the population, in 1875, and in the early 19th century devastated the Great Andamanese population. In Hokkaido , an epidemic of smallpox introduced by Japanese settlers is estimated to have killed 34% of the native Ainu population in 1845. Prevention of future pandemics requires steps to identify future causes of pandemics and to take preventive measures before the disease moves uncontrollably into the human population. For example, influenza is a rapidly evolving disease which has caused pandemics in the past and has potential to cause future pandemics. WHO collates the findings of 144 national influenza centres worldwide which monitor emerging flu viruses. Virus variants which are assessed as likely to represent a significant risk are identified and can then be incorporated into the next seasonal influenza vaccine program. In a press conference on 28 December 2020, Mike Ryan, head of the WHO Emergencies Program, and other officials said the current COVID-19 pandemic is "not necessarily the big one" and "the next pandemic may be more severe." They called for preparation. WHO and the UN have warned the world must tackle the cause of pandemics and not just the health and economic symptoms. There is always a possibility that a disease which has caused epidemics in the past may return in the future. It is also possible that little known diseases may become more virulent; in order to encourage research, a number of organisations which monitor global health have drawn up lists of diseases which may have pandemic potential; see table below. [lower-alpha 5] Coronavirus diseases are a family of usually mild illnesses in humans, including those such as the common cold , that have resulted in outbreaks and pandemics such as the 1889-1890 pandemic , the 2002–2004 SARS outbreak , Middle East respiratory syndrome–related coronavirus and the COVID-19 pandemic . There is widespread concern that members of the coronavirus family, particularly SARS and MERS have the potential to cause future pandemics. Many human coronaviruses have zoonotic origin, their with natural reservoir in bats or rodents, leading to concerns for future spillover events. Following the end of the COVID-19 pandemic Public Health Emergency of International Concern deceleration by WHO, WHO Director General Tedros Ghebreyesus stated he would not hesitate to re-declare COVID-19 a PHEIC should the global situation worsen in the coming months or years. Influenza was first described by the Greek physician Hippocrates in 412 BC. Since the Middle Ages, influenza pandemics have been recorded every 10 to 30 years as the virus mutates to evade immunity. Influenza is an endemic disease , with a fairly constant number of cases which vary seasonally and can, to a certain extent, be predicted. In a typical year, 5–15% of the population contracts influenza. There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year. The 1889–1890 pandemic is estimated to have caused around a million fatalities, and the " Spanish flu " of 1918–1920 eventually infected about one-third of the world's population and caused an estimate 50 million fatalities. The Global Influenza Surveillance and Response System is a global network of laboratories that has for purpose to monitor the spread of influenza with the aim to provide WHO with influenza control information. More than two million respiratory specimens are tested by GISRS annually to monitor the spread and evolution of influenza viruses through a network of about 150 laboratories in 114 countries representing 91% of the world's population. Antibiotic-resistant microorganisms, which sometimes are referred to as " superbugs ", may contribute to the re-emergence of diseases with pandemic potential that are currently well controlled. For example, cases of tuberculosis that are resistant to traditionally effective treatments remain a cause of great concern to health professionals. Every year, nearly half a million new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide. China and India have the highest rate of MDR-TB. WHO reports that approximately 50 million people worldwide are infected with MDR-TB, with 79 percent of those cases resistant to three or more antibiotics. Extensively drug-resistant tuberculosis ( XDR-TB ) was first identified in Africa in 2006 and subsequently discovered to exist in 49 countries. During 2021 there were estimated to be around 25,000 cases XDR-TB worldwide. In the past 20 years, other common bacteria including Staphylococcus aureus , Serratia marcescens and Enterococcus , have developed resistance to a wide range of antibiotics . Antibiotic-resistant organisms have become an important cause of healthcare-associated ( nosocomial ) infections. There are two groups of infectious disease that may be affected by climate change. The first group are vector-borne diseases which are transmitted via insects such as mosquitos or ticks. Some of these diseases, such as malaria , yellow fever , and dengue fever , can have potentially severe health consequences. Climate can affect the distribution of these diseases due to the changing geographic range of their vectors, with the potential to cause serious outbreaks in areas where the disease has not previously been known. The other group comprises water-borne diseases such as cholera, dysentery, and typhoid which may increase in prevalence due to changes in rainfall patterns. The October 2020 'era of pandemics' report by the United Nations ' Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services , written by 22 experts in a variety of fields, said the anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals—in particular birds and mammals —to humans. The "exponential rise" in consumption and trade of commodities such as meat , palm oil , and metals, largely facilitated by developed nations, and a growing human population , are the primary drivers of this destruction. According to Peter Daszak , the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic or any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment." Proposed policy options from the report include taxing meat production and consumption, cracking down on the illegal wildlife trade, removing high-risk species from the legal wildlife trade, eliminating subsidies to businesses that are harmful to the natural world, and establishing a global surveillance network. In June 2021, a team of scientists assembled by the Harvard Medical School Center for Health and the Global Environment warned that the primary cause of pandemics so far, the anthropogenic destruction of the natural world through such activities including deforestation and hunting , is being ignored by world leaders. Permafrost covers a fifth of the northern hemisphere and is made up of soil that has been kept at temperatures below freezing for long periods. Viable samples of viruses have been recovered from thawing permafrost, after having been frozen for many years, sometimes for millennia. There is a remote possibility that a thawed pathogen could infect humans or animals. There is always a possibility that a disease which has caused epidemics in the past may return in the future. It is also possible that little known diseases may become more virulent; in order to encourage research, a number of organisations which monitor global health have drawn up lists of diseases which may have pandemic potential; see table below. [lower-alpha 5] Coronavirus diseases are a family of usually mild illnesses in humans, including those such as the common cold , that have resulted in outbreaks and pandemics such as the 1889-1890 pandemic , the 2002–2004 SARS outbreak , Middle East respiratory syndrome–related coronavirus and the COVID-19 pandemic . There is widespread concern that members of the coronavirus family, particularly SARS and MERS have the potential to cause future pandemics. Many human coronaviruses have zoonotic origin, their with natural reservoir in bats or rodents, leading to concerns for future spillover events. Following the end of the COVID-19 pandemic Public Health Emergency of International Concern deceleration by WHO, WHO Director General Tedros Ghebreyesus stated he would not hesitate to re-declare COVID-19 a PHEIC should the global situation worsen in the coming months or years. Influenza was first described by the Greek physician Hippocrates in 412 BC. Since the Middle Ages, influenza pandemics have been recorded every 10 to 30 years as the virus mutates to evade immunity. Influenza is an endemic disease , with a fairly constant number of cases which vary seasonally and can, to a certain extent, be predicted. In a typical year, 5–15% of the population contracts influenza. There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year. The 1889–1890 pandemic is estimated to have caused around a million fatalities, and the " Spanish flu " of 1918–1920 eventually infected about one-third of the world's population and caused an estimate 50 million fatalities. The Global Influenza Surveillance and Response System is a global network of laboratories that has for purpose to monitor the spread of influenza with the aim to provide WHO with influenza control information. More than two million respiratory specimens are tested by GISRS annually to monitor the spread and evolution of influenza viruses through a network of about 150 laboratories in 114 countries representing 91% of the world's population. Coronavirus diseases are a family of usually mild illnesses in humans, including those such as the common cold , that have resulted in outbreaks and pandemics such as the 1889-1890 pandemic , the 2002–2004 SARS outbreak , Middle East respiratory syndrome–related coronavirus and the COVID-19 pandemic . There is widespread concern that members of the coronavirus family, particularly SARS and MERS have the potential to cause future pandemics. Many human coronaviruses have zoonotic origin, their with natural reservoir in bats or rodents, leading to concerns for future spillover events. Following the end of the COVID-19 pandemic Public Health Emergency of International Concern deceleration by WHO, WHO Director General Tedros Ghebreyesus stated he would not hesitate to re-declare COVID-19 a PHEIC should the global situation worsen in the coming months or years.Influenza was first described by the Greek physician Hippocrates in 412 BC. Since the Middle Ages, influenza pandemics have been recorded every 10 to 30 years as the virus mutates to evade immunity. Influenza is an endemic disease , with a fairly constant number of cases which vary seasonally and can, to a certain extent, be predicted. In a typical year, 5–15% of the population contracts influenza. There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year. The 1889–1890 pandemic is estimated to have caused around a million fatalities, and the " Spanish flu " of 1918–1920 eventually infected about one-third of the world's population and caused an estimate 50 million fatalities. The Global Influenza Surveillance and Response System is a global network of laboratories that has for purpose to monitor the spread of influenza with the aim to provide WHO with influenza control information. More than two million respiratory specimens are tested by GISRS annually to monitor the spread and evolution of influenza viruses through a network of about 150 laboratories in 114 countries representing 91% of the world's population. Antibiotic-resistant microorganisms, which sometimes are referred to as " superbugs ", may contribute to the re-emergence of diseases with pandemic potential that are currently well controlled. For example, cases of tuberculosis that are resistant to traditionally effective treatments remain a cause of great concern to health professionals. Every year, nearly half a million new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide. China and India have the highest rate of MDR-TB. WHO reports that approximately 50 million people worldwide are infected with MDR-TB, with 79 percent of those cases resistant to three or more antibiotics. Extensively drug-resistant tuberculosis ( XDR-TB ) was first identified in Africa in 2006 and subsequently discovered to exist in 49 countries. During 2021 there were estimated to be around 25,000 cases XDR-TB worldwide. In the past 20 years, other common bacteria including Staphylococcus aureus , Serratia marcescens and Enterococcus , have developed resistance to a wide range of antibiotics . Antibiotic-resistant organisms have become an important cause of healthcare-associated ( nosocomial ) infections. There are two groups of infectious disease that may be affected by climate change. The first group are vector-borne diseases which are transmitted via insects such as mosquitos or ticks. Some of these diseases, such as malaria , yellow fever , and dengue fever , can have potentially severe health consequences. Climate can affect the distribution of these diseases due to the changing geographic range of their vectors, with the potential to cause serious outbreaks in areas where the disease has not previously been known. The other group comprises water-borne diseases such as cholera, dysentery, and typhoid which may increase in prevalence due to changes in rainfall patterns. The October 2020 'era of pandemics' report by the United Nations ' Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services , written by 22 experts in a variety of fields, said the anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals—in particular birds and mammals —to humans. The "exponential rise" in consumption and trade of commodities such as meat , palm oil , and metals, largely facilitated by developed nations, and a growing human population , are the primary drivers of this destruction. According to Peter Daszak , the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic or any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment." Proposed policy options from the report include taxing meat production and consumption, cracking down on the illegal wildlife trade, removing high-risk species from the legal wildlife trade, eliminating subsidies to businesses that are harmful to the natural world, and establishing a global surveillance network. In June 2021, a team of scientists assembled by the Harvard Medical School Center for Health and the Global Environment warned that the primary cause of pandemics so far, the anthropogenic destruction of the natural world through such activities including deforestation and hunting , is being ignored by world leaders. Permafrost covers a fifth of the northern hemisphere and is made up of soil that has been kept at temperatures below freezing for long periods. Viable samples of viruses have been recovered from thawing permafrost, after having been frozen for many years, sometimes for millennia. There is a remote possibility that a thawed pathogen could infect humans or animals. In 2016, the commission on a Global Health Risk Framework for the Future estimated that pandemic disease events would cost the global economy over $6 trillion in the 21st century—over $60 billion per year. The same report recommended spending $4.5 billion annually on global prevention and response capabilities to reduce the threat posed by pandemic events, a figure that the World Bank Group raised to $13 billion in a 2019 report. It has been suggested that such costs be paid from a tax on aviation rather than from, e.g., income taxes, given the crucial role of air traffic in transforming local epidemics into pandemics (being the only factor considered in state-of-the-art models of long-range disease transmission ). The COVID-19 pandemic is expected to have a profound negative effect on the global economy , potentially for years to come, with substantial drops in GDP accompanied by increases in unemployment noted around the world. The slowdown of economic activity early in the COVID-19 pandemic had a profound effect on emissions of pollutants and greenhouse gases. Analysis of ice cores taken from the Swiss Alps have revealed a reduction in atmospheric lead pollution over a four-year period corresponding to the years 1349 to 1353 (when the Black Death was ravaging Europe), indicating a reduction in mining and economic activity generally.

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Marburg_virus_disease/html

Marburg virus disease

Marburg virus disease ( MVD ; formerly Marburg hemorrhagic fever ) is a viral hemorrhagic fever in human and non-human primates caused by either of the two Marburgviruses : Marburg virus (MARV) and Ravn virus (RAVV). Its clinical symptoms are very similar to those of Ebola virus disease (EVD). Egyptian fruit bats are believed to be the normal carrier in nature and Marburg virus RNA has been isolated from them. The most detailed study on the frequency, onset, and duration of MVD clinical signs and symptoms was performed during the 1998–2000 mixed MARV/RAVV disease outbreak. A skin rash , red or purple spots (e.g. petechiae or purpura ), bruises , and hematomas (especially around needle injection sites) are typical hemorrhagic manifestations. However, contrary to popular belief, hemorrhage does not lead to hypovolemia and is not the cause of death (total blood loss is minimal except during labor ). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension , disseminated intravascular coagulation , and focal tissue necroses . Clinical phases of Marburg hemorrhagic fever's presentation are described below. Note that phases overlap due to variability between cases.MVD is caused by two viruses; Marburg virus (MARV) and Ravn virus (RAVV) , family Filoviridae. : 458 Marburgviruses are endemic in arid woodlands of equatorial Africa . Most marburgvirus infections were repeatedly associated with people visiting natural caves or working in mines . In 2009, the successful isolation of infectious MARV and RAVV was reported from healthy Egyptian fruit bat caught in caves. This isolation strongly suggests that Old World fruit bats are involved in the natural maintenance of marburgviruses and that visiting bat-infested caves is a risk factor for acquiring marburgvirus infections. Further studies are necessary to establish whether Egyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. Another risk factor is contact with nonhuman primates, although only one outbreak of MVD (in 1967) was due to contact with infected monkeys. Contrary to Ebola virus disease (EVD) , which has been associated with heavy rains after long periods of dry weather, triggering factors for spillover of marburgviruses into the human population have not yet been described.MVD is clinically indistinguishable from Ebola virus disease (EVD) , and it can also easily be confused with many other diseases prevalent in Equatorial Africa , such as other viral hemorrhagic fevers , falciparum malaria , typhoid fever , shigellosis , rickettsial diseases such as typhus , cholera , gram-negative sepsis , borreliosis such as relapsing fever or EHEC enteritis . Other infectious diseases that ought to be included in the differential diagnosis include leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , hemorrhagic smallpox , measles , and fulminant viral hepatitis . Non-infectious diseases that can be confused with MVD are acute promyelocytic leukemia , hemolytic uremic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary hemorrhagic telangiectasia , Kawasaki disease , and even warfarin intoxication. The most important indicator that may lead to the suspicion of MVD at clinical examination is the medical history of the patient, in particular the travel and occupational history (which countries and caves were visited?) and the patient's exposure to wildlife (exposure to bats or bat excrements?). MVD can be confirmed by isolation of marburgviruses from or by detection of marburgvirus antigen or genomic or subgenomic RNAs in patient blood or serum samples during the acute phase of MVD. Marburgvirus isolation is usually performed by inoculation of grivet kidney epithelial Vero E6 or MA-104 cell cultures or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic cytopathic effects . Filovirions can easily be visualized and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences. Immunofluorescence assays are used to confirm marburgvirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore RT-PCR in conjunction with antigen-capture ELISA , which can be performed in field or mobile hospitals and laboratories. Indirect immunofluorescence assays (IFAs) are not used for diagnosis of MVD in the field anymore. [ citation needed ] Marburg virus disease (MVD) is the official name listed in the World Health Organization 's International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg , where MARV was first discovered. Marburg virus disease (MVD) is the official name listed in the World Health Organization 's International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg , where MARV was first discovered. The details of the initial transmission of MVD to humans remain incompletely understood. Transmission most likely occurs from Egyptian fruit bats or another natural host, such as non-human primates or through the consumption of bushmeat , but the specific routes and body fluids involved are unknown. Human-to-human transmission of MVD occurs through direct contact with infected bodily fluids such as blood. Transmission events are relatively rare – there have been only 11 recorded outbreaks of MARV between 1975 and 2011, with one event involving both MARV and RAVV. There are currently no Food and Drug Administration -approved vaccines for the prevention of MVD. Many candidate vaccines have been developed and tested in various animal models. Of those, the most promising ones are DNA vaccines or based on Venezuelan equine encephalitis virus replicons , vesicular stomatitis Indiana virus (VSIV) or filovirus-like particles (VLPs) as all of these candidates could protect nonhuman primates from marburgvirus-induced disease. DNA vaccines have entered clinical trials. Marburgviruses are highly infectious , but not very contagious . They do not get transmitted by aerosol during natural MVD outbreaks. Due to the absence of an approved vaccine, prevention of MVD therefore relies predominantly on quarantine of confirmed or high probability cases, proper personal protective equipment , and sterilization and disinfection . [ citation needed ] The natural maintenance hosts of marburgviruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in Marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source. [ citation needed ] Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids , and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers . Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment , laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.The natural maintenance hosts of marburgviruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in Marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source. [ citation needed ]Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids , and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers . Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment , laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.There is currently no effective marburgvirus-specific therapy for MVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration , administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation , administration of procoagulants late in infection to control hemorrhaging , maintaining oxygen levels, pain management , and administration of antibiotics or antifungals to treat secondary infections. Although supportive care can improve survival chances, marburg virus disease is fatal in the majority of cases. As of 2023 [ update ] the case fatality rate was assessed to be 61.9%. The WHO identifies marburg virus disease as having pandemic potential. Below is a table of outbreaks concerning MVD from 1967 to 2023: MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main , and in Belgrade , Yugoslavia . The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops ) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines . The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine , Emil von Behring . The company, which at the time was owned by Hoechst , was originally set up to develop sera against tetanus and diphtheria . Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment . Secondary cases involved two physicians , a nurse , a post-mortem attendant, and the wife of a veterinarian . All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients. In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe ). He died in a hospital in Johannesburg , South Africa . His girlfriend and an attending nurse were subsequently infected with MVD, but survived. A case of MARV infection occurred in 1980 in Kenya . A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma ) at the base of Mount Elgon (which contains Kitum Cave ), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston 's book The Hot Zone (the French man is referred to under the pseudonym "Charles Monet", whereas the physician is identified under his real name, Shem Musoke). In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu , Kenya . He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa , where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston 's book The Hot Zone (the boy is referred to under the pseudonym "Peter Cardinal"). In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs . The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR (today Russia ). Very little information is publicly available about this MVD case because Ustinov's experiments were classified. A popular science account of this case can be found in Ken Alibek 's book Biohazard . Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR , when a scientist contracted MARV by unknown means. A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa , Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine. In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola , which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity . Contact tracing was complicated by the fact that the country's roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines . Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died. In 2007, four miners became infected with marburgviruses in Kamwenge District , Uganda . The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection. On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda , had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands . The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin . At the time, serologic testing was negative for viral hemorrhagic fever . She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA . In October 2017 an outbreak of Marburg virus disease was detected in Kween District , Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death. A close contact of the second confirmed case traveled to Kampala . It is reported that several hundred people may have been exposed to infection. In August 2021, two months after the re-emergent Ebola epidemic in the Guéckédou prefecture was declared over, a case of the Marburg disease was confirmed by health authorities through laboratory analysis. Other potential case of the disease in a contact awaits official results. This was the first case of the Marburg hemorrhagic fever confirmed to happen in West Africa. The case of Marburg also has been identified in Guéckédou . During the outbreak, a total of one confirmed case, who died ( CFR =100%), and 173 contacts were identified, including 14 high-risk contacts based on exposure. Among them, 172 were followed for a period of 21 days, of which none developed symptoms. One high-risk contact was lost to follow up. Sequencing of an isolate from the Guinean patient showed that this outbreak was caused by the Angola-like Marburg virus. A colony of Egyptian rousettus bats ( reservoir host of Marburg virus ) was found in close proximity (4.5 km) to the village, where the Marburg virus disease outbreak emerged in 2021. Two sampled fruit bats from this colony were PCR-positive on the Marburg virus. In July 2022, preliminary analysis of samples taken from two patients – both deceased – in Ghana indicated the cases were positive for Marburg. However, per standard procedure, the samples were sent to the Pasteur Institute of Dakar for confirmation. On 17 July 2022 the two cases were confirmed by Ghana, which caused the country to declare a Marburg virus disease outbreak. An additional case was identified, bringing the total to three. A disease outbreak was first reported in Equatorial Guinea on 7 February 2023, and on 13 February 2023, it was identified as being Marburg virus disease. It was the first time the disease was detected in the country. Neighbouring Cameroon detected two suspected cases of Marburg virus disease on 13 February 2023, but they were later ruled out. On 25 February, a suspected case of Marburg was reported in the Spanish city of Valencia , however this case was subsequently discounted. As of 4 April 2023, there were 14 confirmed cases and 28 suspected cases, including ten confirmed deaths from the disease in Equatorial Guinea. On 8 June 2023, the World Health Organization declared the outbreak over. In total, 17 laboratory-confirmed cases and 12 deaths were recorded. All the 23 probable cases reportedly died. Four patients recovered from the virus and have been enrolled in a survivors programme to receive psychosocial and other post-recovery support. A Marburg virus disease outbreak in Tanzania was first reported on 21 March 2023 by the Ministry of Health of Tanzania. This was the first time that Tanzania had reported an outbreak of the disease. On 2 June 2023, Tanzania declared the outbreak over. There were 9 total infections, resulting in 6 total deaths. The WHO identifies marburg virus disease as having pandemic potential. Below is a table of outbreaks concerning MVD from 1967 to 2023:MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main , and in Belgrade , Yugoslavia . The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops ) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines . The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine , Emil von Behring . The company, which at the time was owned by Hoechst , was originally set up to develop sera against tetanus and diphtheria . Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment . Secondary cases involved two physicians , a nurse , a post-mortem attendant, and the wife of a veterinarian . All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients. In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe ). He died in a hospital in Johannesburg , South Africa . His girlfriend and an attending nurse were subsequently infected with MVD, but survived. A case of MARV infection occurred in 1980 in Kenya . A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma ) at the base of Mount Elgon (which contains Kitum Cave ), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston 's book The Hot Zone (the French man is referred to under the pseudonym "Charles Monet", whereas the physician is identified under his real name, Shem Musoke). In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu , Kenya . He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa , where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston 's book The Hot Zone (the boy is referred to under the pseudonym "Peter Cardinal"). In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs . The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR (today Russia ). Very little information is publicly available about this MVD case because Ustinov's experiments were classified. A popular science account of this case can be found in Ken Alibek 's book Biohazard . Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR , when a scientist contracted MARV by unknown means. A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa , Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine. In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola , which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity . Contact tracing was complicated by the fact that the country's roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines . Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died. In 2007, four miners became infected with marburgviruses in Kamwenge District , Uganda . The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection. On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda , had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands . The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin . At the time, serologic testing was negative for viral hemorrhagic fever . She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA . In October 2017 an outbreak of Marburg virus disease was detected in Kween District , Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death. A close contact of the second confirmed case traveled to Kampala . It is reported that several hundred people may have been exposed to infection. In August 2021, two months after the re-emergent Ebola epidemic in the Guéckédou prefecture was declared over, a case of the Marburg disease was confirmed by health authorities through laboratory analysis. Other potential case of the disease in a contact awaits official results. This was the first case of the Marburg hemorrhagic fever confirmed to happen in West Africa. The case of Marburg also has been identified in Guéckédou . During the outbreak, a total of one confirmed case, who died ( CFR =100%), and 173 contacts were identified, including 14 high-risk contacts based on exposure. Among them, 172 were followed for a period of 21 days, of which none developed symptoms. One high-risk contact was lost to follow up. Sequencing of an isolate from the Guinean patient showed that this outbreak was caused by the Angola-like Marburg virus. A colony of Egyptian rousettus bats ( reservoir host of Marburg virus ) was found in close proximity (4.5 km) to the village, where the Marburg virus disease outbreak emerged in 2021. Two sampled fruit bats from this colony were PCR-positive on the Marburg virus. In July 2022, preliminary analysis of samples taken from two patients – both deceased – in Ghana indicated the cases were positive for Marburg. However, per standard procedure, the samples were sent to the Pasteur Institute of Dakar for confirmation. On 17 July 2022 the two cases were confirmed by Ghana, which caused the country to declare a Marburg virus disease outbreak. An additional case was identified, bringing the total to three. A disease outbreak was first reported in Equatorial Guinea on 7 February 2023, and on 13 February 2023, it was identified as being Marburg virus disease. It was the first time the disease was detected in the country. Neighbouring Cameroon detected two suspected cases of Marburg virus disease on 13 February 2023, but they were later ruled out. On 25 February, a suspected case of Marburg was reported in the Spanish city of Valencia , however this case was subsequently discounted. As of 4 April 2023, there were 14 confirmed cases and 28 suspected cases, including ten confirmed deaths from the disease in Equatorial Guinea. On 8 June 2023, the World Health Organization declared the outbreak over. In total, 17 laboratory-confirmed cases and 12 deaths were recorded. All the 23 probable cases reportedly died. Four patients recovered from the virus and have been enrolled in a survivors programme to receive psychosocial and other post-recovery support. A Marburg virus disease outbreak in Tanzania was first reported on 21 March 2023 by the Ministry of Health of Tanzania. This was the first time that Tanzania had reported an outbreak of the disease. On 2 June 2023, Tanzania declared the outbreak over. There were 9 total infections, resulting in 6 total deaths. Experimentally, recombinant vesicular stomatitis Indiana virus (VSIV) expressing the glycoprotein of MARV has been used successfully in nonhuman primate models as post-exposure prophylaxis. A vaccine candidate has been effective in nonhuman primates. Experimental therapeutic regimens relying on antisense technology have shown promise, with phosphorodiamidate morpholino oligomers (PMOs) targeting the MARV genome New therapies from Sarepta and Tekmira have also been successfully used in humans as well as primates.

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Crimean-Congo haemorrhagic fever

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Omsk hemorrhagic fever

Omsk hemorrhagic fever is a viral hemorrhagic fever caused by a Flavivirus . It was found in Siberia and was named for an outbreak in the city of Omsk . First records of the new virus appeared around 1940–1943.There are a number of symptoms of the virus. In the first 1–8 days the first phase begins. The symptoms in this phase are: In 1–2 weeks, some people may recover, although others might not. They might experience a focal hemorrhage in mucosa of gingival, uterus , and lungs , a papulovesicular rash on the soft palate, cervical lymphadenopathy (it occurs in the neck which that enlarges the lymph glandular tissue), and occasional neurological involvement. If the patient still has OHF after 3 weeks, then a second wave of symptoms will occur. It also includes signs of encephalitis. In most cases if the sickness does not fade away after this period, the patient will die. Patients that recover from OHF may experience hearing loss, hair loss, and behavioral or psychological difficulties associated with neurological conditions.Omsk haemorrhagic fever virus , Orthoflavivirus omskense Omsk hemorrhagic fever is caused by Omsk hemorrhagic fever virus (OHFV), a member of the Flavivirus family. The current species name is Orthoflavivirus omskense according to International Committee on Taxonomy of Viruses taxonomy standards. The virus was discovered by Mikhail Chumakov and his colleagues between 1945 and 1947 in Omsk , Russia . The infection is found in Western Siberia , in places including Omsk Oblast , Novosibirsk Oblast , Kurgan Oblast , Tyumen Oblast . The virus survives in water and is transferred to humans via contaminated water or an infected tick. The main hosts of OHFV are rodents like the non-native muskrat . OHFV originates in ticks, who then transmit it to rodents by biting them. Humans become infected through tick bites or contact with a muskrat. Humans can also become infected through contact with blood , feces or urine of a dead or sick muskrat (or any type of rat). The virus can also spread through milk from infected goats or sheep. There is no evidence that the virus is contagious among humans. The virus appears to have evolved within the last 1000 years. The viral genomes can be divided into 2 clades—A and B. Clade A has five genotypes and clade B has one. These clades separated about 700 years ago. This separation appears to have occurred in the Kurgan province. Clade A subsequently underwent division into clade C, D and E 230 years ago. Clade C and E appear to have originated in the Novosibirsk and Omsk Provinces respectively. The muskrat Ondatra zibethicus which is highly susceptible to this virus was introduced into this area in the 1930s.The main hosts of OHFV are rodents like the non-native muskrat . OHFV originates in ticks, who then transmit it to rodents by biting them. Humans become infected through tick bites or contact with a muskrat. Humans can also become infected through contact with blood , feces or urine of a dead or sick muskrat (or any type of rat). The virus can also spread through milk from infected goats or sheep. There is no evidence that the virus is contagious among humans.The virus appears to have evolved within the last 1000 years. The viral genomes can be divided into 2 clades—A and B. Clade A has five genotypes and clade B has one. These clades separated about 700 years ago. This separation appears to have occurred in the Kurgan province. Clade A subsequently underwent division into clade C, D and E 230 years ago. Clade C and E appear to have originated in the Novosibirsk and Omsk Provinces respectively. The muskrat Ondatra zibethicus which is highly susceptible to this virus was introduced into this area in the 1930s.Omsk Hemorrhagic Fever could be diagnosed by isolating virus from blood, or by serologic testing using immunosorbent serological assay. OHF rating of fatality is 0.5–3%. Treatment is supportive; there is no specific treatment for OHF. This helps maintain hydration and provides precautions for patients with bleeding disorders.Preventing Omsk Hemorrhagic Fever consists primarily in avoiding being exposed to tick . Persons engaged in camping, farming, forestry, hunting (especially the Siberian muskrat ) are at greater risk and should wear protective clothing or use insect repellent for protection. The same is generally recommended for persons at sheltered locations.

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Crimean-Congo haemorrhagic fever

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Zoonosis

A zoonosis ( / z oʊ ˈ ɒ n ə s ɪ s , ˌ z oʊ ə ˈ n oʊ s ɪ s / ; plural zoonoses ) or zoonotic disease is an infectious disease of humans caused by a pathogen (an infectious agent, such as a bacterium , virus , parasite , or prion ) that can jump from a non-human (usually a vertebrate ) to a human and vice versa. Major modern diseases such as Ebola and salmonellosis are zoonoses. HIV was a zoonotic disease transmitted to humans in the early part of the 20th century, though it has now evolved into a separate human-only disease. Human infection with animal influenza viruses is rare, as they do not transmit easily to or among humans. However, avian and swine influenza viruses in particular possess high zoonotic potential, and these occasionally recombine with human strains of the flu and can cause pandemics such as the 2009 swine flu . Taenia solium infection is one of the neglected tropical diseases with public health and veterinary concern in endemic regions. Zoonoses can be caused by a range of disease pathogens such as emergent viruses , bacteria, fungi and parasites; of 1,415 pathogens known to infect humans, 61% were zoonotic. Most human diseases originated in non-humans; however, only diseases that routinely involve non-human to human transmission, such as rabies , are considered direct zoonoses. Zoonoses have different modes of transmission. In direct zoonosis the disease is directly transmitted from non-humans to humans through media such as air (influenza) or bites and saliva (rabies). In contrast, transmission can also occur via an intermediate species (referred to as a vector ), which carry the disease pathogen without getting sick. When humans infect non-humans, it is called reverse zoonosis or anthroponosis. The term is from Greek : ζῷον zoon "animal" and νόσος nosos "sickness". Host genetics plays an important role in determining which non-human viruses will be able to make copies of themselves in the human body. Dangerous non-human viruses are those that require few mutations to begin replicating themselves in human cells. These viruses are dangerous since the required combinations of mutations might randomly arise in the natural reservoir . The emergence of zoonotic diseases originated with the domestication of animals. Zoonotic transmission can occur in any context in which there is contact with or consumption of animals, animal products, or animal derivatives. This can occur in a companionistic (pets), economic (farming, trade, butchering, etc.), predatory (hunting, butchering, or consuming wild game), or research context. Recently, there has been a rise in frequency of appearance of new zoonotic diseases. "Approximately 1.67 million undescribed viruses are thought to exist in mammals and birds, up to half of which are estimated to have the potential to spill over into humans", says a study led by researchers at the University of California, Davis . According to a report from the United Nations Environment Programme and International Livestock Research Institute a large part of the causes are environmental like climate change , unsustainable agriculture, exploitation of wildlife, and land use change . Others are linked to changes in human society such as an increase in mobility. The organizations propose a set of measures to stop the rise. The most significant zoonotic pathogens causing foodborne diseases are Escherichia coli O157:H7 , Campylobacter , Caliciviridae , and Salmonella . In 2006 a conference held in Berlin focused on the issue of zoonotic pathogen effects on food safety , urging government intervention and public vigilance against the risks of catching food-borne diseases from farm-to-table dining. Many food-borne outbreaks can be linked to zoonotic pathogens. Many different types of food that have an animal origin can become contaminated. Some common food items linked to zoonotic contaminations include eggs, seafood, meat, dairy, and even some vegetables. Outbreaks involving contaminated food should be handled in preparedness plans to prevent widespread outbreaks and to efficiently and effectively contain outbreaks. Contact with farm animals can lead to disease in farmers or others that come into contact with infected farm animals. Glanders primarily affects those who work closely with horses and donkeys. Close contact with cattle can lead to cutaneous anthrax infection, whereas inhalation anthrax infection is more common for workers in slaughterhouses , tanneries , and wool mills . Close contact with sheep who have recently given birth can lead to infection with the bacterium Chlamydia psittaci , causing chlamydiosis (and enzootic abortion in pregnant women), as well as increase the risk of Q fever , toxoplasmosis , and listeriosis , in the pregnant or otherwise immunocompromised . Echinococcosis is caused by a tapeworm, which can spread from infected sheep by food or water contaminated by feces or wool. Avian influenza is common in chickens, and, while it is rare in humans, the main public health worry is that a strain of avian influenza will recombine with a human influenza virus and cause a pandemic like the 1918 Spanish flu . [ citation needed ] In 2017, free-range chickens in the UK were temporarily ordered to remain inside due to the threat of avian influenza. Cattle are an important reservoir of cryptosporidiosis , which mainly affects the immunocompromised. Reports have shown mink can also become infected. In Western countries, hepatitis E burden is largely dependent on exposure to animal products, and pork is a significant source of infection, in this respect. Veterinarians are exposed to unique occupational hazards when it comes to zoonotic disease. In the US, studies have highlighted an increased risk of injuries and lack of veterinary awareness of these hazards. Research has proved the importance for continued clinical veterinarian education on occupational risks associated with musculoskeletal injuries, animal bites, needle-sticks, and cuts. A July 2020 report by the United Nations Environment Programme stated that the increase in zoonotic pandemics is directly attributable to anthropogenic destruction of nature and the increased global demand for meat and that the industrial farming of pigs and chickens in particular will be a primary risk factor for the spillover of zoonotic diseases in the future. Habitat loss of viral reservoir species has been identified as a significant source in at least one spillover event . The wildlife trade may increase spillover risk because it directly increases the number of interactions across animal species, sometimes in small spaces. The origin of the ongoing COVID-19 pandemic is traced to the wet markets in China . Zoonotic disease emergence is demonstrably linked to the consumption of wildlife meat, exacerbated by human encroachment into natural habitats and amplified by the unsanitary conditions of wildlife markets. These markets, where diverse species converge, facilitate the mixing and transmission of pathogens, including those responsible for outbreaks of HIV-1, Ebola, and mpox , and potentially even the COVID-19 pandemic. Notably, small mammals often harbor a vast array of zoonotic bacteria and viruses, yet endemic bacterial transmission among wildlife remains largely unexplored. Therefore, accurately determining the pathogenic landscape of traded wildlife is crucial for guiding effective measures to combat zoonotic diseases and documenting the societal and environmental costs associated with this practice. Pets can transmit a number of diseases. Dogs and cats are routinely vaccinated against rabies . Pets can also transmit ringworm and Giardia , which are endemic in both animal and human populations. Toxoplasmosis is a common infection of cats; in humans it is a mild disease although it can be dangerous to pregnant women. Dirofilariasis is caused by Dirofilaria immitis through mosquitoes infected by mammals like dogs and cats. Cat-scratch disease is caused by Bartonella henselae and Bartonella quintana , which are transmitted by fleas that are endemic to cats. Toxocariasis is the infection of humans by any of species of roundworm , including species specific to dogs ( Toxocara canis ) or cats ( Toxocara cati ). Cryptosporidiosis can be spread to humans from pet lizards, such as the leopard gecko . Encephalitozoon cuniculi is a microsporidial parasite carried by many mammals, including rabbits, and is an important opportunistic pathogen in people immunocompromised by HIV/AIDS , organ transplantation , or CD4+ T-lymphocyte deficiency. Pets may also serve as a reservoir of viral disease and contribute to the chronic presence of certain viral diseases in the human population. For instance, approximately 20% of domestic dogs, cats, and horses carry anti-hepatitis E virus antibodies and thus these animals probably contribute to human hepatitis E burden as well. For non-vulnerable populations (e.g., people who are not immunocompromised) the associated disease burden is, however, small. [ citation needed ] Furthermore, the trade of non domestic animals such as wild animals as pets can also increase the risk of zoonosis spread. Outbreaks of zoonoses have been traced to human interaction with, and exposure to, other animals at fairs , live animal markets , petting zoos , and other settings. In 2005, the Centers for Disease Control and Prevention (CDC) issued an updated list of recommendations for preventing zoonosis transmission in public settings. The recommendations, developed in conjunction with the National Association of State Public Health Veterinarians , include educational responsibilities of venue operators, limiting public animal contact, and animal care and management. Hunting involves humans tracking, chasing, and capturing wild animals, primarily for food or materials like fur. However, other reasons like pest control or managing wildlife populations can also exist. Transmission of zoonotic diseases, those leaping from animals to humans, can occur through various routes: direct physical contact, airborne droplets or particles, bites or vector transport by insects, oral ingestion, or even contact with contaminated environments. Wildlife activities like hunting and trade bring humans closer to dangerous zoonotic pathogens, threatening global health. According to the Center for Diseases Control and Prevention (CDC) hunting and consuming wild animal meat ("bushmeat") in regions like Africa can expose people to infectious diseases due to the types of animals involved, like bats and primates. Unfortunately, common preservation methods like smoking or drying aren't enough to eliminate these risks. Although bushmeat provides protein and income for many, the practice is intricately linked to numerous emerging infectious diseases like Ebola, HIV, and SARS , raising critical public health concerns. A review published in 2022 found evidence that zoonotic spillover linked to wildmeat consumption has been reported across all continents. Kate Jones , Chair of Ecology and Biodiversity at University College London , says zoonotic diseases are increasingly linked to environmental change and human behavior. The disruption of pristine forests driven by logging, mining, road building through remote places, rapid urbanization, and population growth is bringing people into closer contact with animal species they may never have been near before. The resulting transmission of disease from wildlife to humans, she says, is now "a hidden cost of human economic development". In a guest article, published by IPBES , President of the EcoHealth Alliance and zoologist Peter Daszak , along with three co-chairs of the 2019 Global Assessment Report on Biodiversity and Ecosystem Services , Josef Settele, Sandra Díaz , and Eduardo Brondizio, wrote that "rampant deforestation, uncontrolled expansion of agriculture, intensive farming , mining and infrastructure development, as well as the exploitation of wild species have created a 'perfect storm' for the spillover of diseases from wildlife to people." Joshua Moon, Clare Wenham, and Sophie Harman said that there is evidence that decreased biodiversity has an effect on the diversity of hosts and frequency of human-animal interactions with potential for pathogenic spillover. An April 2020 study, published in the Proceedings of the Royal Society ' s Part B journal, found that increased virus spillover events from animals to humans can be linked to biodiversity loss and environmental degradation , as humans further encroach on wildlands to engage in agriculture, hunting, and resource extraction they become exposed to pathogens which normally would remain in these areas. Such spillover events have been tripling every decade since 1980. An August 2020 study, published in Nature , concludes that the anthropogenic destruction of ecosystems for the purpose of expanding agriculture and human settlements reduces biodiversity and allows for smaller animals such as bats and rats, which are more adaptable to human pressures and also carry the most zoonotic diseases, to proliferate. This in turn can result in more pandemics. In October 2020, the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services published its report on the 'era of pandemics' by 22 experts in a variety of fields and concluded that anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals – in particular birds and mammals – to humans. The increased pressure on ecosystems is being driven by the "exponential rise" in consumption and trade of commodities such as meat, palm oil , and metals, largely facilitated by developed nations, and by a growing human population . According to Peter Daszak, the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic, or of any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment." According to a report from the United Nations Environment Programme and International Livestock Research Institute , entitled "Preventing the next pandemic – Zoonotic diseases and how to break the chain of transmission", climate change is one of the 7 human-related causes of the increase in the number of zoonotic diseases. The University of Sydney issued a study, in March 2021, that examines factors increasing the likelihood of epidemics and pandemics like the COVID-19 pandemic. The researchers found that "pressure on ecosystems, climate change and economic development are key factors" in doing so. More zoonotic diseases were found in high-income countries . A 2022 study dedicated to the link between climate change and zoonosis found a strong link between climate change and the epidemic emergence in the last 15 years, as it caused a massive migration of species to new areas, and consequently contact between species which do not normally come in contact with one another. Even in a scenario with weak climatic changes, there will be 15,000 spillover of viruses to new hosts in the next decades. The areas with the most possibilities for spillover are the mountainous tropical regions of Africa and southeast Asia. Southeast Asia is especially vulnerable as it has a large number of bat species that generally do not mix, but could easily if climate change forced them to begin migrating. A 2021 study found possible links between climate change and transmission of COVID-19 through bats. The authors suggest that climate-driven changes in the distribution and robustness of bat species harboring coronaviruses may have occurred in eastern Asian hotspots (southern China, Myanmar, and Laos), constituting a driver behind the evolution and spread of the virus. The most significant zoonotic pathogens causing foodborne diseases are Escherichia coli O157:H7 , Campylobacter , Caliciviridae , and Salmonella . In 2006 a conference held in Berlin focused on the issue of zoonotic pathogen effects on food safety , urging government intervention and public vigilance against the risks of catching food-borne diseases from farm-to-table dining. Many food-borne outbreaks can be linked to zoonotic pathogens. Many different types of food that have an animal origin can become contaminated. Some common food items linked to zoonotic contaminations include eggs, seafood, meat, dairy, and even some vegetables. Outbreaks involving contaminated food should be handled in preparedness plans to prevent widespread outbreaks and to efficiently and effectively contain outbreaks. Contact with farm animals can lead to disease in farmers or others that come into contact with infected farm animals. Glanders primarily affects those who work closely with horses and donkeys. Close contact with cattle can lead to cutaneous anthrax infection, whereas inhalation anthrax infection is more common for workers in slaughterhouses , tanneries , and wool mills . Close contact with sheep who have recently given birth can lead to infection with the bacterium Chlamydia psittaci , causing chlamydiosis (and enzootic abortion in pregnant women), as well as increase the risk of Q fever , toxoplasmosis , and listeriosis , in the pregnant or otherwise immunocompromised . Echinococcosis is caused by a tapeworm, which can spread from infected sheep by food or water contaminated by feces or wool. Avian influenza is common in chickens, and, while it is rare in humans, the main public health worry is that a strain of avian influenza will recombine with a human influenza virus and cause a pandemic like the 1918 Spanish flu . [ citation needed ] In 2017, free-range chickens in the UK were temporarily ordered to remain inside due to the threat of avian influenza. Cattle are an important reservoir of cryptosporidiosis , which mainly affects the immunocompromised. Reports have shown mink can also become infected. In Western countries, hepatitis E burden is largely dependent on exposure to animal products, and pork is a significant source of infection, in this respect. Veterinarians are exposed to unique occupational hazards when it comes to zoonotic disease. In the US, studies have highlighted an increased risk of injuries and lack of veterinary awareness of these hazards. Research has proved the importance for continued clinical veterinarian education on occupational risks associated with musculoskeletal injuries, animal bites, needle-sticks, and cuts. A July 2020 report by the United Nations Environment Programme stated that the increase in zoonotic pandemics is directly attributable to anthropogenic destruction of nature and the increased global demand for meat and that the industrial farming of pigs and chickens in particular will be a primary risk factor for the spillover of zoonotic diseases in the future. Habitat loss of viral reservoir species has been identified as a significant source in at least one spillover event . The wildlife trade may increase spillover risk because it directly increases the number of interactions across animal species, sometimes in small spaces. The origin of the ongoing COVID-19 pandemic is traced to the wet markets in China . Zoonotic disease emergence is demonstrably linked to the consumption of wildlife meat, exacerbated by human encroachment into natural habitats and amplified by the unsanitary conditions of wildlife markets. These markets, where diverse species converge, facilitate the mixing and transmission of pathogens, including those responsible for outbreaks of HIV-1, Ebola, and mpox , and potentially even the COVID-19 pandemic. Notably, small mammals often harbor a vast array of zoonotic bacteria and viruses, yet endemic bacterial transmission among wildlife remains largely unexplored. Therefore, accurately determining the pathogenic landscape of traded wildlife is crucial for guiding effective measures to combat zoonotic diseases and documenting the societal and environmental costs associated with this practice.Pets can transmit a number of diseases. Dogs and cats are routinely vaccinated against rabies . Pets can also transmit ringworm and Giardia , which are endemic in both animal and human populations. Toxoplasmosis is a common infection of cats; in humans it is a mild disease although it can be dangerous to pregnant women. Dirofilariasis is caused by Dirofilaria immitis through mosquitoes infected by mammals like dogs and cats. Cat-scratch disease is caused by Bartonella henselae and Bartonella quintana , which are transmitted by fleas that are endemic to cats. Toxocariasis is the infection of humans by any of species of roundworm , including species specific to dogs ( Toxocara canis ) or cats ( Toxocara cati ). Cryptosporidiosis can be spread to humans from pet lizards, such as the leopard gecko . Encephalitozoon cuniculi is a microsporidial parasite carried by many mammals, including rabbits, and is an important opportunistic pathogen in people immunocompromised by HIV/AIDS , organ transplantation , or CD4+ T-lymphocyte deficiency. Pets may also serve as a reservoir of viral disease and contribute to the chronic presence of certain viral diseases in the human population. For instance, approximately 20% of domestic dogs, cats, and horses carry anti-hepatitis E virus antibodies and thus these animals probably contribute to human hepatitis E burden as well. For non-vulnerable populations (e.g., people who are not immunocompromised) the associated disease burden is, however, small. [ citation needed ] Furthermore, the trade of non domestic animals such as wild animals as pets can also increase the risk of zoonosis spread. Outbreaks of zoonoses have been traced to human interaction with, and exposure to, other animals at fairs , live animal markets , petting zoos , and other settings. In 2005, the Centers for Disease Control and Prevention (CDC) issued an updated list of recommendations for preventing zoonosis transmission in public settings. The recommendations, developed in conjunction with the National Association of State Public Health Veterinarians , include educational responsibilities of venue operators, limiting public animal contact, and animal care and management.Hunting involves humans tracking, chasing, and capturing wild animals, primarily for food or materials like fur. However, other reasons like pest control or managing wildlife populations can also exist. Transmission of zoonotic diseases, those leaping from animals to humans, can occur through various routes: direct physical contact, airborne droplets or particles, bites or vector transport by insects, oral ingestion, or even contact with contaminated environments. Wildlife activities like hunting and trade bring humans closer to dangerous zoonotic pathogens, threatening global health. According to the Center for Diseases Control and Prevention (CDC) hunting and consuming wild animal meat ("bushmeat") in regions like Africa can expose people to infectious diseases due to the types of animals involved, like bats and primates. Unfortunately, common preservation methods like smoking or drying aren't enough to eliminate these risks. Although bushmeat provides protein and income for many, the practice is intricately linked to numerous emerging infectious diseases like Ebola, HIV, and SARS , raising critical public health concerns. A review published in 2022 found evidence that zoonotic spillover linked to wildmeat consumption has been reported across all continents. Kate Jones , Chair of Ecology and Biodiversity at University College London , says zoonotic diseases are increasingly linked to environmental change and human behavior. The disruption of pristine forests driven by logging, mining, road building through remote places, rapid urbanization, and population growth is bringing people into closer contact with animal species they may never have been near before. The resulting transmission of disease from wildlife to humans, she says, is now "a hidden cost of human economic development". In a guest article, published by IPBES , President of the EcoHealth Alliance and zoologist Peter Daszak , along with three co-chairs of the 2019 Global Assessment Report on Biodiversity and Ecosystem Services , Josef Settele, Sandra Díaz , and Eduardo Brondizio, wrote that "rampant deforestation, uncontrolled expansion of agriculture, intensive farming , mining and infrastructure development, as well as the exploitation of wild species have created a 'perfect storm' for the spillover of diseases from wildlife to people." Joshua Moon, Clare Wenham, and Sophie Harman said that there is evidence that decreased biodiversity has an effect on the diversity of hosts and frequency of human-animal interactions with potential for pathogenic spillover. An April 2020 study, published in the Proceedings of the Royal Society ' s Part B journal, found that increased virus spillover events from animals to humans can be linked to biodiversity loss and environmental degradation , as humans further encroach on wildlands to engage in agriculture, hunting, and resource extraction they become exposed to pathogens which normally would remain in these areas. Such spillover events have been tripling every decade since 1980. An August 2020 study, published in Nature , concludes that the anthropogenic destruction of ecosystems for the purpose of expanding agriculture and human settlements reduces biodiversity and allows for smaller animals such as bats and rats, which are more adaptable to human pressures and also carry the most zoonotic diseases, to proliferate. This in turn can result in more pandemics. In October 2020, the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services published its report on the 'era of pandemics' by 22 experts in a variety of fields and concluded that anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals – in particular birds and mammals – to humans. The increased pressure on ecosystems is being driven by the "exponential rise" in consumption and trade of commodities such as meat, palm oil , and metals, largely facilitated by developed nations, and by a growing human population . According to Peter Daszak, the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic, or of any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment." According to a report from the United Nations Environment Programme and International Livestock Research Institute , entitled "Preventing the next pandemic – Zoonotic diseases and how to break the chain of transmission", climate change is one of the 7 human-related causes of the increase in the number of zoonotic diseases. The University of Sydney issued a study, in March 2021, that examines factors increasing the likelihood of epidemics and pandemics like the COVID-19 pandemic. The researchers found that "pressure on ecosystems, climate change and economic development are key factors" in doing so. More zoonotic diseases were found in high-income countries . A 2022 study dedicated to the link between climate change and zoonosis found a strong link between climate change and the epidemic emergence in the last 15 years, as it caused a massive migration of species to new areas, and consequently contact between species which do not normally come in contact with one another. Even in a scenario with weak climatic changes, there will be 15,000 spillover of viruses to new hosts in the next decades. The areas with the most possibilities for spillover are the mountainous tropical regions of Africa and southeast Asia. Southeast Asia is especially vulnerable as it has a large number of bat species that generally do not mix, but could easily if climate change forced them to begin migrating. A 2021 study found possible links between climate change and transmission of COVID-19 through bats. The authors suggest that climate-driven changes in the distribution and robustness of bat species harboring coronaviruses may have occurred in eastern Asian hotspots (southern China, Myanmar, and Laos), constituting a driver behind the evolution and spread of the virus. During most of human prehistory groups of hunter-gatherers were probably very small. Such groups probably made contact with other such bands only rarely. Such isolation would have caused epidemic diseases to be restricted to any given local population, because propagation and expansion of epidemics depend on frequent contact with other individuals who have not yet developed an adequate immune response . To persist in such a population, a pathogen either had to be a chronic infection, staying present and potentially infectious in the infected host for long periods, or it had to have other additional species as reservoir where it can maintain itself until further susceptible hosts are contacted and infected. In fact, for many "human" diseases, the human is actually better viewed as an accidental or incidental victim and a dead-end host . Examples include rabies, anthrax, tularemia, and West Nile fever. Thus, much of human exposure to infectious disease has been zoonotic. Many diseases, even epidemic ones, have zoonotic origin and measles , smallpox , influenza , HIV, and diphtheria are particular examples. Various forms of the common cold and tuberculosis also are adaptations of strains originating in other species. [ citation needed ] Some experts have suggested that all human viral infections were originally zoonotic. Zoonoses are of interest because they are often previously unrecognized diseases or have increased virulence in populations lacking immunity. The West Nile virus first appeared in the United States in 1999 , in the New York City area. Bubonic plague is a zoonotic disease, as are salmonellosis , Rocky Mountain spotted fever , and Lyme disease . A major factor contributing to the appearance of new zoonotic pathogens in human populations is increased contact between humans and wildlife. This can be caused either by encroachment of human activity into wilderness areas or by movement of wild animals into areas of human activity. An example of this is the outbreak of Nipah virus in peninsular Malaysia, in 1999, when intensive pig farming began within the habitat of infected fruit bats. The unidentified infection of these pigs amplified the force of infection, transmitting the virus to farmers, and eventually causing 105 human deaths. Similarly, in recent times avian influenza and West Nile virus have spilled over into human populations probably due to interactions between the carrier host and domestic animals. [ citation needed ] Highly mobile animals, such as bats and birds, may present a greater risk of zoonotic transmission than other animals due to the ease with which they can move into areas of human habitation. Because they depend on the human host for part of their life-cycle, diseases such as African schistosomiasis , river blindness , and elephantiasis are not defined as zoonotic, even though they may depend on transmission by insects or other vectors . The first vaccine against smallpox by Edward Jenner in 1800 was by infection of a zoonotic bovine virus which caused a disease called cowpox . Jenner had noticed that milkmaids were resistant to smallpox. Milkmaids contracted a milder version of the disease from infected cows that conferred cross immunity to the human disease. Jenner abstracted an infectious preparation of 'cowpox' and subsequently used it to inoculate persons against smallpox. As a result of vaccination, smallpox has been eradicated globally, and mass inoculation against this disease ceased in 1981. There are a variety of vaccine types, including traditional inactivated pathogen vaccines, subunit vaccines , live attenuated vaccines . There are also new vaccine technologies such as viral vector vaccines and DNA/RNA vaccines , which include many of the COVID-19 vaccines .

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Notifiable_diseases_in_the_United_Kingdom/html

Notifiable diseases in the United Kingdom

A notifiable disease is one which the law requires to be reported to government authorities. In England and Wales, notification of infectious diseases is a statutory duty for registered medical practitioners and laboratories, under the Public Health (Control of Disease) Act 1984 and (in England) the Health Protection (Notification) Regulations 2010. Similar provision, albeit with a different list of diseases, is made for Wales in the Health Protection (Notification) (Wales) Regulations 2010. Medical practitioners are required to notify their local authority of diseases on the list in writing within three days, or if the situation is urgent, by telephone within 24 hours. For Scotland, similar provision is made by the Public Health etc. (Scotland) Act 2008 . The diseases notifiable in England to local authorities under the Health Protection (Notification) Regulations 2010 are: The causative organisms which the laboratories shall notify to the proper authority under the Health Protection (Notification) Regulations 2010 are: [ citation needed ]

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Dengue_fever/html

Dengue fever

Dengue fever is a mosquito-borne tropical disease caused by dengue virus . It is frequently asymptomatic ; if symptoms appear they typically begin 3 to 14 days after infection. These may include a high fever , headache , vomiting , muscle and joint pains , and a characteristic skin itching and skin rash . Recovery generally takes two to seven days. In a small proportion of cases, the disease develops into severe dengue (previously known as dengue hemorrhagic fever or dengue shock syndrome) with bleeding , low levels of blood platelets , blood plasma leakage, and dangerously low blood pressure . Dengue virus has four confirmed serotypes ; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications. The symptoms of dengue resemble many other diseases including malaria , influenza , and Zika . Blood tests are available to confirm the diagnosis including detecting viral RNA , or antibodies to the virus. There is no specific treatment for dengue fever. In mild cases, treatment is focused on treating pain symptoms. Severe cases of dengue require hospitalisation; treatment of acute dengue is supportive and includes giving fluid either by mouth or intravenously . Dengue is spread by several species of female mosquitoes of the Aedes genus , principally Aedes aegypti . Infection can be prevented by mosquito elimination and the prevention of bites. Two types of dengue vaccine have been approved and are commercially available. Dengvaxia became available in 2016 but it is only recommended to prevent re-infection in individuals who have been previously infected. The second vaccine, Qdenga, became available in 2022 and is suitable for adults, adolescents and children from four years of age. The earliest descriptions of a dengue outbreak date from 1779; its viral cause and spread were understood by the early 20th century. Already endemic in more than one hundred countries, dengue is spreading from tropical and subtropical regions to the Iberian Peninsula and the southern states of the US, partly attributed to climate change. It is classified as a neglected tropical disease . During 2023, more than 5 million infections were reported, with more than 5,000 dengue-related deaths. As most cases are asymptomatic or mild, the actual numbers of dengue cases and deaths are under-reported. Typically, people infected with dengue virus are asymptomatic (80%) or have only mild symptoms such as an uncomplicated fever. Others have more severe illness (5%), and in a small proportion it is life-threatening. The incubation period (time between exposure and onset of symptoms) ranges from 3 to 14 days, but most often it is 4 to 7 days. The characteristic symptoms of mild dengue are sudden-onset fever, headache (typically located behind the eyes), muscle and joint pains, nausea, vomiting, swollen glands and a rash. If this progresses to severe dengue the symptoms are severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums or nose, fatigue, restlessness, blood in vomit or stool, extreme thirst, pale and cold skin, and feelings of weakness. The course of infection is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue , (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . The course of infection is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue , (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . Dengue virus (DENV) is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it's also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga . Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. Dengue virus (DENV) is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it's also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga . Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. The World Health Organization 's International Classification of Diseases divides dengue fever into two classes: uncomplicated and severe. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage. Severe dengue can develop suddenly, sometimes after a few days as the fever subsides. Leakage of plasma from the capillaries results in extreme low blood pressure and hypovolemic shock ; Patients with severe plasma leakage may have fluid accumulation in the lungs or abdomen , insufficient protein in the blood , or thickening of the blood . Severe dengue is a medical emergency which can cause damage to organs, leading to multiple organ failure and death. Mild cases of dengue fever can easily be confused with several common diseases including Influenza , measles , chikungunya , and zika . Dengue, chikungunya and zika share the same mode of transmission ( Aedes mosquitoes) and are often endemic in the same regions, so that it is possible to be infected simultaneously by more than one disease. For travellers, dengue fever diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics . Warning symptoms of severe dengue include abdominal pain, persistent vomiting, odema, bleeding, lethargy, and liver enlargement. Once again, these symptoms can be confused with other diseases such as malaria, gastroenteritis, leptospirosis, and typhus. Blood tests can be used to confirm a diagnosis of dengue. During the first few days of infection, enzyme-linked immunosorbent assay ( ELISA ) can be used to detect the NS1 antigen ; however this antigen is produced by all flaviviruses. Four or five days into the infection, it is possible to reliably detect anti-dengue IgM antibodies, but this does not determine the serotype. Nucleic acid amplification tests provide the most reliable method of diagnosis. As of March 2024, there is no specific antiviral treatment available for dengue fever. Most cases of dengue fever have mild symptoms, and recovery takes place in a few days. No treatment is required for these cases. Acetaminophen (Paracetamol, Tylenol ) may be used to relieve mild fever or pain. Other common pain relievers, including aspirin , ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve) should be avoided as they can increase the risk of bleeding complications. For moderate illness, those who can drink, are passing urine, have no warning signs and are otherwise reasonably healthy can be monitored carefully at home. Supportive care with analgesics, fluid replacement, and bed rest are recommended. Severe dengue is a life-threatening emergency, requiring hospitalization and potentially intensive care. Warning signs include dehydration , decreasing platelets and increasing hematocrit . Treatment modes include intravenous fluids, and transfusion with platelets or plasma. Most people with dengue recover without any ongoing problems. The risk of death among those with severe dengue is 0.8% to 2.5%, and with adequate treatment this is less than 1%. However, those who develop significantly low blood pressure may have a fatality rate of up to 26%. The risk of death among children less than five years old is four times greater than among those over the age of 10. Elderly people are also at higher risk of a poor outcome. As of March 2023, dengue is endemic in more than 100 countries with cases reported in every continent with the exception of Antarctica. The Americas, Southeast Asia and the Western Pacific regions are the most seriously affected. It is difficult to estimate the full extent of the disease, as many cases are mild and not correctly diagnosed. WHO currently estimates that 3.9 billion people are at risk of dengue infection. In 2013, it was estimated that 390 million dengue infections occur every year, with 500,000 of these developing severe symptoms and 25,000 deaths. Generally, areas where dengue is endemic have only one serotype of the virus in circulation. The disease is said to be hyperendemic in areas where more than one serotype is circulating; this increases the risk of severe disease on a second or subsequent infection. Infections are most commonly acquired in urban environments where the virus is primarily transmitted by the mosquito species Aedes aegypti . This species has adapted to the urban environment, is generally found close to human habitation, prefers humans as its host, and takes advantage of small bodies of standing water (such as tanks and buckets) in which to breed. In rural settings the virus is transmitted to humans by A. aegypti and other related mosquitoes such as Aedes albopictus . Both these species have expanding ranges. Dengue has increased in incidence in recent decades, with WHO recording a ten fold increase between 2010 and 2019 (from 500,000 to 5 million recorded cases). This increase is tied closely to the increasing range of Aedes mosquitoes, which is attributed to a combination of urbanization , population growth, and an increasingly warm climate . In endemic areas, dengue infections peak when rainfall is optimal for mosquito breeding. The disease infects all races, sexes, and ages equally. In endemic areas, the infection is most commonly seen in children who then acquire a lifelong partial immunity. The first historical record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (266–420) which referred to a "water poison" associated with flying insects. The principal mosquito vector of dengue, Aedes aegypti , spread out of Africa in the 15th to 19th centuries due to the slave trade and consequent expansion of international trading. There have been descriptions of epidemics of dengue-like illness in the 17th century, and it is likely that epidemics in Jakarta , Cairo , and Philadelphia during the 18th century were caused by dengue. It is assumed that dengue was constantly present in many tropical urban centres throughout the 19th and early 20th centuries, even though significant outbreaks were infrequent. The marked spread of dengue during and after the Second World War has been attributed partly to disruption caused by the war, and partly to subsequent urbanisation in south-east Asia. As novel serotypes were introduced to regions already endemic with dengue, outbreaks of severe disease followed. The severe hemorrhagic form of the disease was first reported in the Philippines in 1953; by the 1970s, it had become recognised as a major cause of child mortality in Southeast Asia. In Central and South America, the Aedes mosquito had been eradicated in the 1950s; however the eradication program was discontinued in the 1970s and the diesase re-established itself in the region during the 1980s, becoming hyperendemic and causing significant epidemics. Dengue has continued to increase in prevalence during the 21st century, as the mosquito vector continues to expand its range. This is attributed partly to continuing urbanisation, and partly to the impact of a warmer climate. The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga (in full kidingapopo , "disease caused by an evil spirit"). The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy , and the disease was known as "dandy fever". The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush , in a 1789 report of the 1780 epidemic in Philadelphia , due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only after 1828. Other historical terms include "breakheart fever" and "la dengue". Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga (in full kidingapopo , "disease caused by an evil spirit"). The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy , and the disease was known as "dandy fever". The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush , in a 1789 report of the 1780 epidemic in Philadelphia , due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only after 1828. Other historical terms include "breakheart fever" and "la dengue". Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". Research directions include dengue pathogenesis (the process by which the disease develops in humans), as well as the biology, ecology and behaviour of the mosquito vector. Improved diagnostics would enable faster and more appropriate treatment. Attempts are ongoing to develop an antiviral medicine targeting the NS3 or NS5 proteins. In addition to the two vaccines which are already available, several vaccine candidates are in development. Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus. Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months. International Anti-Dengue Day is observed every year on 15 June in a number of countries. The idea was first agreed upon in 2010 with the first event held in Jakarta , Indonesia, in 2011. Further events were held in 2012 in Yangon , Myanmar, and in 2013 in Vietnam . Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998. A National Dengue Day is held in India annually on 16 May. A study estimate that the global burden of dengue in 2013 amounted to US$8·9 billion. Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus. Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months. International Anti-Dengue Day is observed every year on 15 June in a number of countries. The idea was first agreed upon in 2010 with the first event held in Jakarta , Indonesia, in 2011. Further events were held in 2012 in Yangon , Myanmar, and in 2013 in Vietnam . Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998. A National Dengue Day is held in India annually on 16 May. A study estimate that the global burden of dengue in 2013 amounted to US$8·9 billion.

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Crimean-Congo haemorrhagic fever

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MRNA vaccine

An mRNA vaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen -encoding mRNA into immune cells , which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen (such as a virus ) or by a cancer cell . These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells. Reactogenicity , the tendency of a vaccine to produce adverse reactions, is similar to that of conventional non-RNA vaccines. People susceptible to an autoimmune response may have an adverse reaction to messenger RNA vaccines. The advantages of mRNA vaccines over traditional vaccines are ease of design, speed and lower cost of production, the induction of both cellular and humoral immunity , and lack of interaction with the genomic DNA . While some messenger RNA vaccines, such as the Pfizer–BioNTech COVID-19 vaccine , have the disadvantage of requiring ultracold storage before distribution, other mRNA vaccines, such as the Moderna vaccine, or the Walvax COVID-19 vaccine used in Indonesia (and the now abandoned CureVac vaccine candidate, as well), do not have such requirements. In RNA therapeutics , messenger RNA vaccines have attracted considerable interest as COVID-19 vaccines . In December 2020, Pfizer–BioNTech and Moderna obtained authorization for their mRNA-based COVID-19 vaccines. On 2 December, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first medicines regulator to approve an mRNA vaccine, authorizing the Pfizer–BioNTech vaccine for widespread use. On 11 December, the US Food and Drug Administration (FDA) issued an emergency use authorization for the Pfizer–BioNTech vaccine and a week later similarly authorized the Moderna vaccine. In 2023 the Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for their discoveries concerning modified nucleosides that enabled the development of effective mRNA vaccines against COVID-19. The first successful transfection of designed mRNA packaged within a liposomal nanoparticle into a cell was published in 1989. "Naked" (or unprotected) lab-made mRNA was injected a year later into the muscle of mice. These studies were the first evidence that in vitro transcribed mRNA with a chosen gene was able to deliver the genetic information to produce a desired protein within living cell tissue and led to the concept proposal of messenger RNA vaccines. Liposome-encapsulated mRNA encoding a viral antigen was shown in 1993 to stimulate T cells in mice. The following year self-amplifying mRNA was developed by including both a viral antigen and replicase encoding gene. The method was used in mice to elicit both a humoral and cellular immune response against a viral pathogen. The next year mRNA encoding a tumor antigen was shown to elicit a similar immune response against cancer cells in mice. The first human clinical trial using ex vivo dendritic cells transfected with mRNA encoding tumor antigens ( therapeutic cancer mRNA vaccine ) was started in 2001. Four years later, the successful use of modified nucleosides as a method to transport mRNA inside cells without setting off the body's defense system was reported. Clinical trial results of an mRNA vaccine directly injected into the body against cancer cells were reported in 2008. BioNTech in 2008, and Moderna in 2010, were founded to develop mRNA biotechnologies. The US research agency DARPA launched at this time the biotechnology research program ADEPT to develop emerging technologies for the US military . The agency recognized the potential of nucleic acid technology for defense against pandemics and began to invest in the field. DARPA grants were seen as a vote of confidence that in turn encouraged other government agencies and private investors to invest in mRNA technology. DARPA awarded at the time a $25 million grant to Moderna. The first human clinical trials using an mRNA vaccine against an infectious agent ( rabies ) began in 2013. Over the next few years, clinical trials of mRNA vaccines for a number of other viruses were started. mRNA vaccines for human use were studied for infectious agents such as influenza , Zika virus , cytomegalovirus , and Chikungunya virus . The COVID-19 pandemic , and sequencing of the causative virus SARS-CoV-2 at the beginning of 2020, led to the rapid development of the first approved mRNA vaccines. BioNTech and Moderna in December of the same year obtained approval for their mRNA-based COVID-19 vaccines . On 2 December, seven days after its final eight-week trial, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first global medicines regulator in history to approve an mRNA vaccine, granting emergency authorization for Pfizer–BioNTech's BNT162b2 COVID-19 vaccine for widespread use. On 11 December, the FDA gave emergency use authorization for the Pfizer–BioNTech COVID-19 vaccine and a week later similar approval for the Moderna COVID-19 vaccine . Other mRNA vaccines continue to be developed, since the approval of the first mRNA vaccines. Moderna announced the development of mRNA vaccines for 15 diseases: Chikungunya virus , COVID-19, Crimean-Congo haemorrhagic fever , Dengue , Ebola virus disease , HIV , Malaria , Marburg virus disease , Lassa fever , Middle East respiratory syndrome coronavirus (MERS-CoV) , Nipah and henipaviral diseases, Rift Valley fever , Severe fever with Thrombocytopenia syndrome , Tuberculosis and Zika . The first successful transfection of designed mRNA packaged within a liposomal nanoparticle into a cell was published in 1989. "Naked" (or unprotected) lab-made mRNA was injected a year later into the muscle of mice. These studies were the first evidence that in vitro transcribed mRNA with a chosen gene was able to deliver the genetic information to produce a desired protein within living cell tissue and led to the concept proposal of messenger RNA vaccines. Liposome-encapsulated mRNA encoding a viral antigen was shown in 1993 to stimulate T cells in mice. The following year self-amplifying mRNA was developed by including both a viral antigen and replicase encoding gene. The method was used in mice to elicit both a humoral and cellular immune response against a viral pathogen. The next year mRNA encoding a tumor antigen was shown to elicit a similar immune response against cancer cells in mice. The first human clinical trial using ex vivo dendritic cells transfected with mRNA encoding tumor antigens ( therapeutic cancer mRNA vaccine ) was started in 2001. Four years later, the successful use of modified nucleosides as a method to transport mRNA inside cells without setting off the body's defense system was reported. Clinical trial results of an mRNA vaccine directly injected into the body against cancer cells were reported in 2008. BioNTech in 2008, and Moderna in 2010, were founded to develop mRNA biotechnologies. The US research agency DARPA launched at this time the biotechnology research program ADEPT to develop emerging technologies for the US military . The agency recognized the potential of nucleic acid technology for defense against pandemics and began to invest in the field. DARPA grants were seen as a vote of confidence that in turn encouraged other government agencies and private investors to invest in mRNA technology. DARPA awarded at the time a $25 million grant to Moderna. The first human clinical trials using an mRNA vaccine against an infectious agent ( rabies ) began in 2013. Over the next few years, clinical trials of mRNA vaccines for a number of other viruses were started. mRNA vaccines for human use were studied for infectious agents such as influenza , Zika virus , cytomegalovirus , and Chikungunya virus . The COVID-19 pandemic , and sequencing of the causative virus SARS-CoV-2 at the beginning of 2020, led to the rapid development of the first approved mRNA vaccines. BioNTech and Moderna in December of the same year obtained approval for their mRNA-based COVID-19 vaccines . On 2 December, seven days after its final eight-week trial, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first global medicines regulator in history to approve an mRNA vaccine, granting emergency authorization for Pfizer–BioNTech's BNT162b2 COVID-19 vaccine for widespread use. On 11 December, the FDA gave emergency use authorization for the Pfizer–BioNTech COVID-19 vaccine and a week later similar approval for the Moderna COVID-19 vaccine . Other mRNA vaccines continue to be developed, since the approval of the first mRNA vaccines. Moderna announced the development of mRNA vaccines for 15 diseases: Chikungunya virus , COVID-19, Crimean-Congo haemorrhagic fever , Dengue , Ebola virus disease , HIV , Malaria , Marburg virus disease , Lassa fever , Middle East respiratory syndrome coronavirus (MERS-CoV) , Nipah and henipaviral diseases, Rift Valley fever , Severe fever with Thrombocytopenia syndrome , Tuberculosis and Zika . The goal of a vaccine is to stimulate the adaptive immune system to create antibodies that precisely target that particular pathogen . The markers on the pathogen that the antibodies target are called antigens . Traditional vaccines stimulate an antibody response by injecting either antigens , an attenuated (weakened) virus, an inactivated (dead) virus, or a recombinant antigen-encoding viral vector (harmless carrier virus with an antigen transgene ) into the body. These antigens and viruses are prepared and grown outside the body. In contrast, mRNA vaccines introduce a short-lived synthetically created fragment of the RNA sequence of a virus into the individual being vaccinated. These mRNA fragments are taken up by dendritic cells through phagocytosis . The dendritic cells use their internal machinery ( ribosomes ) to read the mRNA and produce the viral antigens that the mRNA encodes. The body degrades the mRNA fragments within a few days of introduction. Although non-immune cells can potentially also absorb vaccine mRNA, produce antigens, and display the antigens on their surfaces, dendritic cells absorb the mRNA globules much more readily. The mRNA fragments are translated in the cytoplasm and do not affect the body's genomic DNA, located separately in the cell nucleus . Once the viral antigens are produced by the host cell, the normal adaptive immune system processes are followed. Antigens are broken down by proteasomes . Class I and class II MHC molecules then attach to the antigen and transport it to the cellular membrane, "activating" the dendritic cell. Once activated, dendritic cells migrate to lymph nodes , where they present the antigen to T cells and B cells . This triggers the production of antibodies specifically targeted to the antigen, ultimately resulting in immunity . The central component of a mRNA vaccine is its mRNA construct. The in vitro transcribed mRNA is generated from an engineered plasmid DNA, which has an RNA polymerase promoter and sequence which corresponds to the mRNA construct. By combining T7 phage RNA polymerase and the plasmid DNA, the mRNA can be transcribed in the lab. Efficacy of the vaccine is dependent on the stability and structure of the designed mRNA. The in vitro transcribed mRNA has the same structural components as natural mRNA in eukaryotic cells . It has a 5' cap , a 5'-untranslated region (UTR) and 3'-UTR , an open reading frame (ORF), which encodes the relevant antigen, and a 3'-poly(A) tail . By modifying these different components of the synthetic mRNA, the stability and translational ability of the mRNA can be enhanced, and in turn, the efficacy of the vaccine improved. The mRNA can be improved by using synthetic 5'-cap analogues which enhance the stability and increase protein translation. Similarly, regulatory elements in the 5'-untranslated region and the 3'-untranslated region can be altered, and the length of the poly(A) tail optimized, to stabilize the mRNA and increase protein production. The mRNA nucleotides can be modified to both decrease innate immune activation and increase the mRNA's half-life in the host cell. The nucleic acid sequence and codon usage impacts protein translation. Enriching the sequence with guanine-cytosine content improves mRNA stability and half-life and, in turn, protein production. Replacing rare codons with synonymous codons frequently used by the host cell also enhances protein production. For a vaccine to be successful, sufficient mRNA must enter the host cell cytoplasm to stimulate production of the specific antigens. Entry of mRNA molecules, however, faces a number of difficulties. Not only are mRNA molecules too large to cross the cell membrane by simple diffusion , they are also negatively charged like the cell membrane, which causes a mutual electrostatic repulsion . Additionally, mRNA is easily degraded by RNAases in skin and blood. Various methods have been developed to overcome these delivery hurdles. The method of vaccine delivery can be broadly classified by whether mRNA transfer into cells occurs within ( in vivo ) or outside ( ex vivo ) the organism. Dendritic cells display antigens on their surfaces , leading to interactions with T cells to initiate an immune response. Dendritic cells can be collected from patients and programmed with the desired mRNA, then administered back into patients to create an immune response. The simplest way that ex vivo dendritic cells take up mRNA molecules is through endocytosis , a fairly inefficient pathway in the laboratory setting that can be significantly improved through electroporation . Since the discovery that the direct administration of in vitro transcribed mRNA leads to the expression of antigens in the body, in vivo approaches have been investigated. They offer some advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting dendritic cells from patients and by imitating a regular infection. Different routes of injection , such as into the skin , blood , or muscles , result in varying levels of mRNA uptake, making the choice of administration route a critical aspect of in vivo delivery. One study showed, in comparing different routes, that lymph node injection leads to the largest T-cell response. Naked mRNA injection means that the delivery of the vaccine is only done in a buffer solution . This mode of mRNA uptake has been known since the 1990s. The first worldwide clinical studies used intradermal injections of naked mRNA for vaccination. A variety of methods have been used to deliver naked mRNA, such as subcutaneous, intravenous, and intratumoral injections. Although naked mRNA delivery causes an immune response, the effect is relatively weak, and after injection the mRNA is often rapidly degraded. Cationic polymers can be mixed with mRNA to generate protective coatings called polyplexes . These protect the recombinant mRNA from ribonucleases and assist its penetration in cells. Protamine is a natural cationic peptide and has been used to encapsulate mRNA for vaccination. [ non-primary source needed ] The first time the FDA approved the use of lipid nanoparticles as a drug delivery system was in 2018, when the agency approved the first siRNA drug, Onpattro . Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key technical barriers in delivering the mRNA molecule into the host cell. Research into using lipids to deliver siRNA to cells became a foundation for similar research into using lipids to deliver mRNA. However, new lipids had to be invented to encapsulate mRNA strands, which are much longer than siRNA strands. Principally, the lipid provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid's outer layer allows the targeting of desired cell types through ligand interactions. However, many studies have also highlighted the difficulty of studying this type of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of nanoparticles in terms of cellular intake. The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system . One issue with lipid nanoparticles is that several of the breakthroughs leading to the practical use of that technology involve the use of microfluidics . Microfluidic reaction chambers are difficult to scale up, since the entire point of microfluidics is to exploit the microscale behaviors of liquids. The only way around this obstacle is to run an extensive number of microfluidic reaction chambers in parallel, a novel task requiring custom-built equipment. For COVID-19 mRNA vaccines, this was the main manufacturing bottleneck. Pfizer used such a parallel approach to solve the scaling problem. After verifying that impingement jet mixers could not be directly scaled up, Pfizer made about 100 of the little mixers (each about the size of a U.S. half-dollar coin ), connected them together with pumps and filters with a "maze of piping," and set up a computer system to regulate flow and pressure through the mixers. Another issue, with the large-scale use of this delivery method, is the availability of the novel lipids used to create lipid nanoparticles, especially ionizable cationic lipids. Before 2020, such lipids were manufactured in small quantities measured in grams or kilograms, and they were used for medical research and a handful of drugs for rare conditions. As the safety and efficacy of mRNA vaccines became clear in 2020, the few companies able to manufacture the requisite lipids were confronted with the challenge of scaling up production to respond to orders for several tons of lipids. In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar immunological responses. Typical RNA viruses used as vectors include retroviruses , lentiviruses , alphaviruses and rhabdoviruses , each of which can differ in structure and function. Clinical studies have utilized such viruses on a range of diseases in model animals such as mice , chicken and primates . Dendritic cells display antigens on their surfaces , leading to interactions with T cells to initiate an immune response. Dendritic cells can be collected from patients and programmed with the desired mRNA, then administered back into patients to create an immune response. The simplest way that ex vivo dendritic cells take up mRNA molecules is through endocytosis , a fairly inefficient pathway in the laboratory setting that can be significantly improved through electroporation . Since the discovery that the direct administration of in vitro transcribed mRNA leads to the expression of antigens in the body, in vivo approaches have been investigated. They offer some advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting dendritic cells from patients and by imitating a regular infection. Different routes of injection , such as into the skin , blood , or muscles , result in varying levels of mRNA uptake, making the choice of administration route a critical aspect of in vivo delivery. One study showed, in comparing different routes, that lymph node injection leads to the largest T-cell response. Naked mRNA injection means that the delivery of the vaccine is only done in a buffer solution . This mode of mRNA uptake has been known since the 1990s. The first worldwide clinical studies used intradermal injections of naked mRNA for vaccination. A variety of methods have been used to deliver naked mRNA, such as subcutaneous, intravenous, and intratumoral injections. Although naked mRNA delivery causes an immune response, the effect is relatively weak, and after injection the mRNA is often rapidly degraded. Cationic polymers can be mixed with mRNA to generate protective coatings called polyplexes . These protect the recombinant mRNA from ribonucleases and assist its penetration in cells. Protamine is a natural cationic peptide and has been used to encapsulate mRNA for vaccination. [ non-primary source needed ] The first time the FDA approved the use of lipid nanoparticles as a drug delivery system was in 2018, when the agency approved the first siRNA drug, Onpattro . Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key technical barriers in delivering the mRNA molecule into the host cell. Research into using lipids to deliver siRNA to cells became a foundation for similar research into using lipids to deliver mRNA. However, new lipids had to be invented to encapsulate mRNA strands, which are much longer than siRNA strands. Principally, the lipid provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid's outer layer allows the targeting of desired cell types through ligand interactions. However, many studies have also highlighted the difficulty of studying this type of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of nanoparticles in terms of cellular intake. The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system . One issue with lipid nanoparticles is that several of the breakthroughs leading to the practical use of that technology involve the use of microfluidics . Microfluidic reaction chambers are difficult to scale up, since the entire point of microfluidics is to exploit the microscale behaviors of liquids. The only way around this obstacle is to run an extensive number of microfluidic reaction chambers in parallel, a novel task requiring custom-built equipment. For COVID-19 mRNA vaccines, this was the main manufacturing bottleneck. Pfizer used such a parallel approach to solve the scaling problem. After verifying that impingement jet mixers could not be directly scaled up, Pfizer made about 100 of the little mixers (each about the size of a U.S. half-dollar coin ), connected them together with pumps and filters with a "maze of piping," and set up a computer system to regulate flow and pressure through the mixers. Another issue, with the large-scale use of this delivery method, is the availability of the novel lipids used to create lipid nanoparticles, especially ionizable cationic lipids. Before 2020, such lipids were manufactured in small quantities measured in grams or kilograms, and they were used for medical research and a handful of drugs for rare conditions. As the safety and efficacy of mRNA vaccines became clear in 2020, the few companies able to manufacture the requisite lipids were confronted with the challenge of scaling up production to respond to orders for several tons of lipids. In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar immunological responses. Typical RNA viruses used as vectors include retroviruses , lentiviruses , alphaviruses and rhabdoviruses , each of which can differ in structure and function. Clinical studies have utilized such viruses on a range of diseases in model animals such as mice , chicken and primates . Naked mRNA injection means that the delivery of the vaccine is only done in a buffer solution . This mode of mRNA uptake has been known since the 1990s. The first worldwide clinical studies used intradermal injections of naked mRNA for vaccination. A variety of methods have been used to deliver naked mRNA, such as subcutaneous, intravenous, and intratumoral injections. Although naked mRNA delivery causes an immune response, the effect is relatively weak, and after injection the mRNA is often rapidly degraded. Cationic polymers can be mixed with mRNA to generate protective coatings called polyplexes . These protect the recombinant mRNA from ribonucleases and assist its penetration in cells. Protamine is a natural cationic peptide and has been used to encapsulate mRNA for vaccination. [ non-primary source needed ] The first time the FDA approved the use of lipid nanoparticles as a drug delivery system was in 2018, when the agency approved the first siRNA drug, Onpattro . Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key technical barriers in delivering the mRNA molecule into the host cell. Research into using lipids to deliver siRNA to cells became a foundation for similar research into using lipids to deliver mRNA. However, new lipids had to be invented to encapsulate mRNA strands, which are much longer than siRNA strands. Principally, the lipid provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid's outer layer allows the targeting of desired cell types through ligand interactions. However, many studies have also highlighted the difficulty of studying this type of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of nanoparticles in terms of cellular intake. The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system . One issue with lipid nanoparticles is that several of the breakthroughs leading to the practical use of that technology involve the use of microfluidics . Microfluidic reaction chambers are difficult to scale up, since the entire point of microfluidics is to exploit the microscale behaviors of liquids. The only way around this obstacle is to run an extensive number of microfluidic reaction chambers in parallel, a novel task requiring custom-built equipment. For COVID-19 mRNA vaccines, this was the main manufacturing bottleneck. Pfizer used such a parallel approach to solve the scaling problem. After verifying that impingement jet mixers could not be directly scaled up, Pfizer made about 100 of the little mixers (each about the size of a U.S. half-dollar coin ), connected them together with pumps and filters with a "maze of piping," and set up a computer system to regulate flow and pressure through the mixers. Another issue, with the large-scale use of this delivery method, is the availability of the novel lipids used to create lipid nanoparticles, especially ionizable cationic lipids. Before 2020, such lipids were manufactured in small quantities measured in grams or kilograms, and they were used for medical research and a handful of drugs for rare conditions. As the safety and efficacy of mRNA vaccines became clear in 2020, the few companies able to manufacture the requisite lipids were confronted with the challenge of scaling up production to respond to orders for several tons of lipids. In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar immunological responses. Typical RNA viruses used as vectors include retroviruses , lentiviruses , alphaviruses and rhabdoviruses , each of which can differ in structure and function. Clinical studies have utilized such viruses on a range of diseases in model animals such as mice , chicken and primates . mRNA vaccines offer specific advantages over traditional vaccines . Because mRNA vaccines are not constructed from an active pathogen (or even an inactivated pathogen), they are non-infectious. In contrast, traditional vaccines require the production of pathogens, which, if done at high volumes, could increase the risks of localized outbreaks of the virus at the production facility. Another biological advantage of mRNA vaccines is that since the antigens are produced inside the cell, they stimulate cellular immunity , as well as humoral immunity . mRNA vaccines have the production advantage that they can be designed swiftly. Moderna designed their mRNA-1273 vaccine for COVID-19 in 2 days. They can also be manufactured faster, more cheaply, and in a more standardized fashion (with fewer error rates in production), which can improve responsiveness to serious outbreaks. The Pfizer–BioNTech vaccine originally required 110 days to mass-produce (before Pfizer began to optimize the manufacturing process to only 60 days), which was substantially faster than traditional flu and polio vaccines. Within that larger timeframe, the actual production time is only about 22 days: two weeks for molecular cloning of DNA plasmids and purification of DNA, four days for DNA-to-RNA transcription and purification of mRNA, and four days to encapsulate mRNA in lipid nanoparticles followed by fill and finish . The majority of the days needed for each production run are allocated to rigorous quality control at each stage. In addition to sharing the advantages of theoretical DNA vaccines over established traditional vaccines , mRNA vaccines also have additional advantages over DNA vaccines. The mRNA is translated in the cytosol , so there is no need for the RNA to enter the cell nucleus , and the risk of being integrated into the host genome is averted. Modified nucleosides (for example, pseudouridines , 2'-O-methylated nucleosides) can be incorporated to mRNA to suppress immune response stimulation to avoid immediate degradation and produce a more persistent effect through enhanced translation capacity. The open reading frame (ORF) and untranslated regions (UTR) of mRNA can be optimized for different purposes (a process called sequence engineering of mRNA), for example through enriching the guanine-cytosine content or choosing specific UTRs known to increase translation. An additional ORF coding for a replication mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed. mRNA vaccines offer specific advantages over traditional vaccines . Because mRNA vaccines are not constructed from an active pathogen (or even an inactivated pathogen), they are non-infectious. In contrast, traditional vaccines require the production of pathogens, which, if done at high volumes, could increase the risks of localized outbreaks of the virus at the production facility. Another biological advantage of mRNA vaccines is that since the antigens are produced inside the cell, they stimulate cellular immunity , as well as humoral immunity . mRNA vaccines have the production advantage that they can be designed swiftly. Moderna designed their mRNA-1273 vaccine for COVID-19 in 2 days. They can also be manufactured faster, more cheaply, and in a more standardized fashion (with fewer error rates in production), which can improve responsiveness to serious outbreaks. The Pfizer–BioNTech vaccine originally required 110 days to mass-produce (before Pfizer began to optimize the manufacturing process to only 60 days), which was substantially faster than traditional flu and polio vaccines. Within that larger timeframe, the actual production time is only about 22 days: two weeks for molecular cloning of DNA plasmids and purification of DNA, four days for DNA-to-RNA transcription and purification of mRNA, and four days to encapsulate mRNA in lipid nanoparticles followed by fill and finish . The majority of the days needed for each production run are allocated to rigorous quality control at each stage. In addition to sharing the advantages of theoretical DNA vaccines over established traditional vaccines , mRNA vaccines also have additional advantages over DNA vaccines. The mRNA is translated in the cytosol , so there is no need for the RNA to enter the cell nucleus , and the risk of being integrated into the host genome is averted. Modified nucleosides (for example, pseudouridines , 2'-O-methylated nucleosides) can be incorporated to mRNA to suppress immune response stimulation to avoid immediate degradation and produce a more persistent effect through enhanced translation capacity. The open reading frame (ORF) and untranslated regions (UTR) of mRNA can be optimized for different purposes (a process called sequence engineering of mRNA), for example through enriching the guanine-cytosine content or choosing specific UTRs known to increase translation. An additional ORF coding for a replication mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed. Because mRNA is fragile, some vaccines must be kept at very low temperatures to avoid degrading and thus giving little effective immunity to the recipient. Pfizer–BioNTech's BNT162b2 mRNA vaccine has to be kept between −80 and −60 °C (−112 and −76 °F) . Moderna says their mRNA-1273 vaccine can be stored between −25 and −15 °C (−13 and 5 °F) , which is comparable to a home freezer, and that it remains stable between 2 and 8 °C (36 and 46 °F) for up to 30 days. In November 2020, Nature reported, "While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions." Several platforms are being studied that may allow storage at higher temperatures. Before 2020, no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so there was a risk of unknown effects. The 2020 COVID-19 pandemic required faster production capability of mRNA vaccines, made them attractive to national health organisations, and led to debate about the type of initial authorization mRNA vaccines should get (including emergency use authorization or expanded access authorization ) after the eight-week period of post-final human trials. Reactogenicity is similar to that of conventional, non-RNA vaccines. However, those susceptible to an autoimmune response may have an adverse reaction to mRNA vaccines. The mRNA strands in the vaccine may elicit an unintended immune reaction – this entails the body believing itself to be sick, and the person feeling as if they are as a result. To minimize this, mRNA sequences in mRNA vaccines are designed to mimic those produced by host cells. Strong but transient reactogenic effects were reported in trials of novel COVID-19 mRNA vaccines; most people will not experience severe side effects which include fever and fatigue. Severe side effects are defined as those that prevent daily activity. Because mRNA is fragile, some vaccines must be kept at very low temperatures to avoid degrading and thus giving little effective immunity to the recipient. Pfizer–BioNTech's BNT162b2 mRNA vaccine has to be kept between −80 and −60 °C (−112 and −76 °F) . Moderna says their mRNA-1273 vaccine can be stored between −25 and −15 °C (−13 and 5 °F) , which is comparable to a home freezer, and that it remains stable between 2 and 8 °C (36 and 46 °F) for up to 30 days. In November 2020, Nature reported, "While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions." Several platforms are being studied that may allow storage at higher temperatures. Before 2020, no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so there was a risk of unknown effects. The 2020 COVID-19 pandemic required faster production capability of mRNA vaccines, made them attractive to national health organisations, and led to debate about the type of initial authorization mRNA vaccines should get (including emergency use authorization or expanded access authorization ) after the eight-week period of post-final human trials. Reactogenicity is similar to that of conventional, non-RNA vaccines. However, those susceptible to an autoimmune response may have an adverse reaction to mRNA vaccines. The mRNA strands in the vaccine may elicit an unintended immune reaction – this entails the body believing itself to be sick, and the person feeling as if they are as a result. To minimize this, mRNA sequences in mRNA vaccines are designed to mimic those produced by host cells. Strong but transient reactogenic effects were reported in trials of novel COVID-19 mRNA vaccines; most people will not experience severe side effects which include fever and fatigue. Severe side effects are defined as those that prevent daily activity. The COVID-19 mRNA vaccines from Moderna and Pfizer–BioNTech have efficacy rates of 90 to 95 percent [ citation needed ] . Prior mRNA, drug trials on pathogens other than COVID-19 were not effective and had to be abandoned in the early phases of trials. The reason for the efficacy of the new mRNA vaccines is not clear. Physician-scientist Margaret Liu stated that the efficacy of the new COVID-19 mRNA vaccines could be due to the "sheer volume of resources" that went into development, or that the vaccines might be "triggering a nonspecific inflammatory response to the mRNA that could be heightening its specific immune response, given that the modified nucleoside technique reduced inflammation but hasn't eliminated it completely", and that "this may also explain the intense reactions such as aches and fevers reported in some recipients of the mRNA SARS-CoV-2 vaccines". These reactions though severe were transient and another view is that they were believed to be a reaction to the lipid drug delivery molecules. There is misinformation implying that mRNA vaccines could alter DNA in the nucleus. mRNA in the cytosol is very rapidly degraded before it would have time to gain entry into the cell nucleus. In fact, mRNA vaccines must be stored at very low temperature and free from RNAses to prevent mRNA degradation. Retrovirus can be single-stranded RNA (just as many SARS-CoV-2 vaccines are single-stranded RNA) which enters the cell nucleus and uses reverse transcriptase to make DNA from the RNA in the cell nucleus. A retrovirus has mechanisms to be imported into the nucleus, but other mRNA (such as the vaccine) lack these mechanisms. Once inside the nucleus, creation of DNA from RNA cannot occur without a reverse transcriptase and appropriate primers , which both accompany a retrovirus, but which would not be present for other exogenous mRNA (such as a vaccine) even if it could enter the nucleus. mRNA vaccines use either non-amplifying (conventional) mRNA or self-amplifying mRNA. Pfizer–BioNTech and Moderna vaccines use non-amplifying mRNA. Both mRNA types continue to be investigated as vaccine methods against other potential pathogens and cancer. The initial mRNA vaccines use a non-amplifying mRNA construct. Non-amplifying mRNA has only one open reading frame that codes for the antigen of interest. The total amount of mRNA available to the cell is equal to the amount delivered by the vaccine. Dosage strength is limited by the amount of mRNA that can be delivered by the vaccine. Non-amplifying vaccines replace uridine with N1-Methylpseudouridine in an attempt to reduce toxicity. Self-amplifying mRNA (saRNA) vaccines replicate their mRNA after transfection. Self-amplifying mRNA has two open reading frames . The first frame, like conventional mRNA, codes for the antigen of interest. The second frame codes for an RNA-dependent RNA polymerase (and its helper proteins) which replicates the mRNA construct in the cell. This allows smaller vaccine doses. The mechanisms and consequently the evaluation of self-amplifying mRNA may be different, as self-amplifying mRNA is a much bigger molecule. SaRNA vaccines being researched include a malaria vaccine . Gritstone bio started in 2021 a phase 1 trial of an saRNA COVID-19 vaccine, used as a booster vaccine . The vaccine is designed to target both the spike protein of the SARS‑CoV‑2 virus, and viral proteins that may be less prone to genetic variation, to provide greater protection against SARS‑CoV‑2 variants. saRNA vaccines must use uridine, which is required for reproduction to occur. The initial mRNA vaccines use a non-amplifying mRNA construct. Non-amplifying mRNA has only one open reading frame that codes for the antigen of interest. The total amount of mRNA available to the cell is equal to the amount delivered by the vaccine. Dosage strength is limited by the amount of mRNA that can be delivered by the vaccine. Non-amplifying vaccines replace uridine with N1-Methylpseudouridine in an attempt to reduce toxicity. Self-amplifying mRNA (saRNA) vaccines replicate their mRNA after transfection. Self-amplifying mRNA has two open reading frames . The first frame, like conventional mRNA, codes for the antigen of interest. The second frame codes for an RNA-dependent RNA polymerase (and its helper proteins) which replicates the mRNA construct in the cell. This allows smaller vaccine doses. The mechanisms and consequently the evaluation of self-amplifying mRNA may be different, as self-amplifying mRNA is a much bigger molecule. SaRNA vaccines being researched include a malaria vaccine . Gritstone bio started in 2021 a phase 1 trial of an saRNA COVID-19 vaccine, used as a booster vaccine . The vaccine is designed to target both the spike protein of the SARS‑CoV‑2 virus, and viral proteins that may be less prone to genetic variation, to provide greater protection against SARS‑CoV‑2 variants. saRNA vaccines must use uridine, which is required for reproduction to occur.

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Bolivian_hemorrhagic_fever/html

Bolivian hemorrhagic fever

Machupo virus Bolivian hemorrhagic fever ( BHF ), also known as black typhus or Ordog Fever , is a hemorrhagic fever and zoonotic infectious disease originating in Bolivia after infection by Machupo mammarenavirus . BHF was first identified in 1963 as an ambisense RNA virus of the Arenaviridae family, by a research group led by Karl Johnson . The mortality rate is estimated at 5 to 30 percent. Due to its pathogenicity , Machupo virus requires Biosafety Level Four conditions, the highest level. During the period between February and March 2007, some 20 suspected BHF cases (3 fatal) were reported to the Servicio Departamental de Salud (SEDES) in Beni Department , Bolivia. In February 2008, at least 200 suspected new cases (12 fatal) were reported to SEDES. In November 2011, a second case was confirmed near the departmental capital of Trinidad , and a serosurvey was conducted to determine the extent of Machupo virus infections in the department. A SEDES expert involved in the survey expressed his concerns about the expansion of the virus to other provinces outside the endemic regions of Mamoré and Iténez provinces . The disease was first encountered in 1962, in the Bolivian village of San Joaquín, hence the name "Bolivian" Hemorrhagic Fever. When initial investigations failed to find an arthropod carrier, other sources were sought before finally determining that the disease was carried by infected mice. Although mosquitoes were not the cause as originally suspected, the extermination of mosquitoes using DDT to prevent malaria proved to be indirectly responsible for the outbreak in that the accumulation of DDT in various animals along the food chain led to a shortage of cats in the village; subsequently, a mouse plague erupted in the village, leading to an epidemic. The vector is the large vesper mouse ( Calomys callosus ), a rodent indigenous to northern Bolivia. Infected animals are asymptomatic and shed the virus in excreta, thereby infecting humans. Evidence of person-to-person transmission of BHF exists but is believed to be rare. The infection has a slow onset with fever , malaise , headache and myalgia , very similar to Malaria symptoms. Petechiae (blood spots) on the upper body and bleeding from the nose and gums are observed when the disease progresses to the hemorrhagic phase, usually within seven days of onset. Severe hemorrhagic or neurologic symptoms are observed in about one third of patients. Neurologic symptoms involve tremors, delirium, and convulsions. The mortality rate is about 25%. Measures to reduce contact between the vesper mouse and humans may have contributed to limiting the number of outbreaks, with no cases identified between 1973 and 1994. Although there are no cures or vaccine for the disease, a vaccine developed for the genetically related Junín virus which causes Argentine hemorrhagic fever has shown evidence of cross-reactivity to Machupo virus, and may therefore be an effective prophylactic measure for people at high risk of infection. Post infection (and providing that the person survives the infection), those that have contracted BHF are usually immune to further infection of the disease. The disease was first encountered in 1962, in the Bolivian village of San Joaquín, hence the name "Bolivian" Hemorrhagic Fever. When initial investigations failed to find an arthropod carrier, other sources were sought before finally determining that the disease was carried by infected mice. Although mosquitoes were not the cause as originally suspected, the extermination of mosquitoes using DDT to prevent malaria proved to be indirectly responsible for the outbreak in that the accumulation of DDT in various animals along the food chain led to a shortage of cats in the village; subsequently, a mouse plague erupted in the village, leading to an epidemic. The vector is the large vesper mouse ( Calomys callosus ), a rodent indigenous to northern Bolivia. Infected animals are asymptomatic and shed the virus in excreta, thereby infecting humans. Evidence of person-to-person transmission of BHF exists but is believed to be rare. The infection has a slow onset with fever , malaise , headache and myalgia , very similar to Malaria symptoms. Petechiae (blood spots) on the upper body and bleeding from the nose and gums are observed when the disease progresses to the hemorrhagic phase, usually within seven days of onset. Severe hemorrhagic or neurologic symptoms are observed in about one third of patients. Neurologic symptoms involve tremors, delirium, and convulsions. The mortality rate is about 25%. Measures to reduce contact between the vesper mouse and humans may have contributed to limiting the number of outbreaks, with no cases identified between 1973 and 1994. Although there are no cures or vaccine for the disease, a vaccine developed for the genetically related Junín virus which causes Argentine hemorrhagic fever has shown evidence of cross-reactivity to Machupo virus, and may therefore be an effective prophylactic measure for people at high risk of infection. Post infection (and providing that the person survives the infection), those that have contracted BHF are usually immune to further infection of the disease. Bolivian hemorrhagic fever was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program in 1969. Albert Nickel, a 53-year old animal caretaker at Fort Detrick , died in 1964 from the disease after being bitten by an infected mouse. Nickel Place, on Fort Detrick, is named in his honor. It was also under research by the Soviet Union, under the Biopreparat bureau. Investigational vaccines exist for Argentine hemorrhagic fever and RVF; however, neither is approved by FDA or commonly available in the United States. The structure of the attachment glycoprotein has been determined by X-ray crystallography and this glycoprotein is likely to be an essential component of any successful vaccine.

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Kyasanur_Forest_disease/html

Kyasanur Forest disease

Kyasanur forest disease ( KFD ) is a tick-borne viral haemorrhagic fever endemic to South-western part of India. The disease is caused by a virus belonging to the family Flaviviridae . KFDV is transmitted to humans through the bite of infected hard ticks ( Haemaphysalis spinigera ) which act as a reservoir of KFDV.The symptoms of the disease include a high fever with frontal headaches, chills, severe muscle pain, vomiting, and other gastrointestinal symptoms. Bleeding problems may occur 3–4 days after initial symptom onset. Patients may experience abnormally low blood pressure, and low platelet, red blood cell, and white blood cell count. After 1–2 weeks of symptoms, some patients recover without complication. However, the illness is biphasic for a subset of patients (10-20%) who experience a second wave of symptoms at the beginning of the third week. These symptoms include fever and signs of neurological manifestations, such as severe headache, mental disturbances, tremors, and vision deficits. The convalescent period is typically very long, lasting several months. Muscle aches and weakness also occur during this period, and the patient is unable to engage in physical activities.Kyasanur Forest virus The KFD virus is a typical flavivirus measuring about 40-60 nm in diameter. The genome of KFDV consists of 10,774 nucleotides of single-stranded, positive-sense RNA encoding a single polyprotein that is cleaved post-translationally into three structural (C, prM/M and E) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5) proteins. The genome of KFDV is very similar (>92% homologous) to that of Alkhurma Hemorrhagic Fever Virus which is primarily found in Saudi Arabia . These two species both belong to the family Flaviviridae and diverged over 700 years ago and have thus remained geographically separated. A variety of animals are thought to be reservoir hosts for the disease, including porcupines, rats, squirrels, mice, and shrews. Monkeys are the main amplifying hosts for KFD virus and they are also affected by the virus. The surili Presbytis entellus and the bonnet macaque are very susceptible to the KFD virus. They develop tremendous viremia and infect the ticks. The vector for disease transmission is Haemaphysalis spinigera , a forest tick . Humans contract infection from the bite of nymphs of the tick. Man is a terminal host and there no human-to-human transmission because the human domestic environment does not sustain the ticks.Kyasanur Forest virus The KFD virus is a typical flavivirus measuring about 40-60 nm in diameter. The genome of KFDV consists of 10,774 nucleotides of single-stranded, positive-sense RNA encoding a single polyprotein that is cleaved post-translationally into three structural (C, prM/M and E) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5) proteins. The genome of KFDV is very similar (>92% homologous) to that of Alkhurma Hemorrhagic Fever Virus which is primarily found in Saudi Arabia . These two species both belong to the family Flaviviridae and diverged over 700 years ago and have thus remained geographically separated. A variety of animals are thought to be reservoir hosts for the disease, including porcupines, rats, squirrels, mice, and shrews. Monkeys are the main amplifying hosts for KFD virus and they are also affected by the virus. The surili Presbytis entellus and the bonnet macaque are very susceptible to the KFD virus. They develop tremendous viremia and infect the ticks. The vector for disease transmission is Haemaphysalis spinigera , a forest tick . Humans contract infection from the bite of nymphs of the tick. Man is a terminal host and there no human-to-human transmission because the human domestic environment does not sustain the ticks.The pathogenesis of KFDV is not completely understood . Research using mice models found that KFDV primarily replicated in the brain. Other research has expanded on this by described neurological changes that occurred within infected organisms. This experiment was completed by using KFDV-infected mice and discovered that KFDV caused gliosis , inflammation, and cell death in the brain. They posited that KFDV could be primarily a neuropathic disease and other symptoms are due to this pathogenesis. In earlier days suspected case were confirmed in a laboratory by serum inoculation into suckling mice (Swiss Albino mice) and subsequent death of mice was leveled as KFD Positive case. Other methods of diagnosis included hemagglutination inhibition (HI), complement fixation , neutralization tests . However, new research has introduced more efficient molecular based methods to diagnose KFDV. These methods include: RT-PCR, nested RT-PCR , TaqMan-based real-time RT-PCR , Immunoglobin M antibodies and Immunoglobin G detection by ELISA . The two methods involving RT- PCR are able to function by attaching a primer to the NS-5 gene, which is highly conserved among the genus to which KFDV belongs. PCR positivity is limited to 8–10 days from the onset of symptoms. The ELISA based methods allows for the detections of anti-KFDV antibodies in patients typically from 5th day of onset of symptoms up to 3 months. Prevention is by vaccination, as well as preventive measures such as protective clothing and tick population control. The vaccine for KFDV consists of formalin -inactivated KFDV. The vaccine has a 62.4% effectiveness rate for individuals who receive two doses. For individuals who receive an additional dose, the effectiveness increases to 82.9%. Specific antiviral treatments are not available as of 2022. The spill-over of Kyasanur forest disease happens at the crossroads of the animal-human interaction, especially villages adjoining forest areas and inter-state borders. People who frequently visit the forest areas of the Western Ghats region such as forest guards and officials, range forest officer (RFO), forest watchers, shepherds, firewood collectors, dry leaf collectors, hunters, people who handle dead animal carcasses, travelers who camp in the forest areas, tribal communities living inside the forest areas (Jenu kurubas and Betta kurubas), cashew nut workers especially those who engage in cleaning the dry leaves before the harvest season (seen in Pali and Mauxi outbreaks, North Goa), and areca nut farm workers working in infected tick areas will have a high risk of acquiring KFD infection. People who live in the KFD endemic areas and refuse to take KFD vaccination are at risk in contracting the infection.The disease was first reported from Kattinakere village forest which is in the Kyasanur forest range of Karnataka in India in March 1957. When the officials visited the Kattinakere forest and discovered the diseases they noticed a sign board informing that this was the Kyasanur forest range. Hence the name. The disease first manifested as an epizootic outbreak among monkeys, killing several of them in the year 1957. Hence the disease is also locally known as "monkey disease" or "monkey fever". The similarity with Russian spring-summer encephalitis was noted by the British neurovirologist Hubert Webb and the possibility of migratory birds carrying the disease was raised. Studies began to look for the possible species that acted as reservoirs for the virus and the agents responsible for transmission. Subsequent studies failed to find any involvement of migratory birds, although the possibility of their role in initial establishment was not ruled out. The virus was found to be quite distinctive and not closely related to the Russian virus strains. Antigenic relatedness is, however, close to many other strains including the Omsk hemorrhagic fever (OHF) and birds from Siberia have been found to show an antigenic response to KFD virus. Sequence based studies note the distinctiveness of OHF. Early studies in India were conducted in collaboration with the US Army Medical Research Unit and this led to controversy and conspiracy theories. Subsequent studies based on sequencing found that the Alkhurma virus found in Saudi Arabia is closely related. In 1989 a patient in Nanjianin, China was found with fever symptoms and in 2009 its viral gene sequence was found to exactly match with that of the KFD reference virus of 1957. This has been questioned, though, since the Indian virus shows variations in sequence over time and the exact match with the virus sequence of 1957 and the Chinese virus of 1989 is not expected. This study also found using immune response tests that birds and humans in the region appeared to have been exposed to the virus. Another study has suggested that the virus is recent in origin dating the nearest common ancestor of it and related viruses to around 1942, based on the estimated rate of sequence substitutions. The study also raises the possibility of bird involvement in long-distance transfer. It appears that these viruses diverged 700 years ago. A recent outbreak in 2020, claimed two lives in Siddapura , Karnataka. The peak season for this disease in Malnad is from March till May but has been observed to peak earlier in the year as well. There were a total of 55 reported cases in Shivamogga district, Karntaka. The disease initially reported from Shimoga district of Karnataka which is a primitive sylvan territory in Western Ghats of India. The disease spread out to other districts of Karnataka involving districts of Chikkamagalore, Uttara Kannada, Dakshina Kannada, Udupi, Chamarajanagar (2012), Belagavi (2016). In 2013, KFDV was detected in monkey autopsies from Nilgiris district of Tamil Nadu state. Monkey deaths and human cases have now been reported from three neighbouring states bordering Karnataka, i.e., Wayanad (2013) and Malappuram districts of Kerala (2014), North Goa district of Goa state (2015), and Sindhudurg district of Maharashtra (2016). There are reported serological evidence for KFD detected in humans in other parts of India, namely Kutch and Saurashtra regions of Gujarat state, Kingaon and Parbatpur of West Bengal state. A seroprevalence study in Andaman and Nicobar islands in 2002 revealed a high prevalence of hemagglutination inhibition (HI) antibodies against KFDV. The disease has a fatality rate of 3-10%, and it affects 400-500 people annually. The disease was first noted at Kyasanur village near Sagar in Shivamogga district of Karnataka. The virus has been detected in monkeys in parts of Bandipur National Park (Chamarajnagar) and parts of the Nilgiris. Human infection occurred in Bandipur through handling of dead monkeys that were infected. A human carrier was also detected in Wayanad (Kerala). The disease has shown its presence in the adjacent states of Karnataka including Kerala, Maharashtra, Goa, Tamil Nadu and Gujarat.

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Crimean-Congo haemorrhagic fever

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Ribavirin

AU : X (High risk) 1-[(2"R",3"R",4"S",5"R")-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1"H"-1,2,4-triazole-3-carboxamide OC[C@@H](O1)[C@@H](O)[C@@H](O)[C@@H]1N2N=C(C(N)=O)N=C2 InChI=1S/C8H12N4O5/c9-6(16)7-10-2-12(11-7)8-5(15)4(14)3(1-13)17-8/h2-5,8,13-15H,1H2,(H2,9,16)/t3-,4-,5-,8-/m1/s1 Y Key:IWUCXVSUMQZMFG-AFCXAGJDSA-N Y Ribavirin , also known as tribavirin , is an antiviral medication used to treat RSV infection , hepatitis C and some viral hemorrhagic fevers . For hepatitis C, it is used in combination with other medications such as simeprevir , sofosbuvir , peginterferon alfa-2b or peginterferon alfa-2a . Among the viral hemorrhagic fevers it is sometimes used for Lassa fever , Crimean–Congo hemorrhagic fever , and Hantavirus infection but should not be used for Ebola or Marburg infections. Ribavirin is taken orally (swallowed by mouth) or inhaled . Despite widespread usage, since the 2010s it has faced scrutiny for a lack of efficacy in treating viral infections it has historically been prescribed for. Common side effects include tiredness, headache, nausea, fever, muscle pains, and an irritable mood. Serious side effects include red blood cell breakdown , liver problems , and allergic reactions . Use during pregnancy results in harm to the baby. Effective birth control is recommended for both males and females for at least seven months during and after use. The mechanism of action of ribavirin is not entirely clear. Ribavirin was patented in 1971 and approved for medical use in 1986. It is on the World Health Organization's List of Essential Medicines . It is available as a generic medication . Ribavirin is used primarily to treat chronic hepatitis C and viral hemorrhagic fevers (which is an orphan indication in most countries). Its efficacy for these purposes has been questioned: it has an FDA boxed warning against its use as a monotherapy (sole drug) for chronic hepatitis C, and thus it may only be prescribed in the United States as an adjunct to one or more other medications. Its efficacy against other viruses, including those that cause viral hemorrhagic fever, has not been conclusively demonstrated, and it is not approved in the United States for treatment of viruses other than HCV. For chronic hepatitis C, the oral (capsule or tablet) form of ribavirin is used only in combination with pegylated interferon alfa . Statins may improve this combination's efficacy in treating hepatitis C. When possible, genotyping of the specific viral strain is done; ribavirin is only used as a dose-escalating [lower-alpha 1] adjuvant to specific combinations of genotypes and other medications. Acute hepatitis C infection (within the first 6 months) often does not require immediate treatment, as many infections eventually resolve without treatment. When the decision is made to treat acute hepatitis C, ribavirin may be used as an adjunct to several drug combinations. However, other medications are preferred. Ribavirin is the only known treatment for a variety of viral hemorrhagic fevers , including Lassa fever , Crimean-Congo hemorrhagic fever , Venezuelan hemorrhagic fever , and Hantavirus infection, although data regarding these infections are scarce and the drug might be effective only in early stages. It is noted by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) that "Ribavirin has poor in vitro and in vivo activity against the filoviruses ( Ebola and Marburg ) and the flaviviruses ( dengue , yellow fever , Omsk hemorrhagic fever , and Kyasanur forest disease )" The aerosol form has been used in the past to treat respiratory syncytial virus -related diseases in children, although the evidence to support this is rather weak. Despite questions surrounding its efficacy, ribavirin remains the only antiviral known to be effective in treating Lassa fever. It has been used (in combination with ketamine , midazolam , and amantadine ) in treatment of rabies . Experimental data indicate that ribavirin may have useful activity against canine distemper and poxviruses . Ribavirin has also been used as a treatment for herpes simplex virus . One small study found that ribavirin treatment reduced the severity of herpes outbreaks and promoted recovery, as compared with placebo treatment. Another study found that ribavirin potentiated the antiviral effect of acyclovir . Some interest has been seen in its possible use as a treatment for cancers with elevated eukaryotic translation initiation factor eIF4E, especially acute myeloid leukemia (AML) as well as in head and neck cancers. Ribavirin targeted eIF4E in AML patients in monotherapy and combination studies and this corresponded to objective clinical responses including complete remissions. Ribavirin resistance in AML patients arose leading to loss of eIF4E targeting and relapse. Resistance was caused by deactivation of ribavirin through its glucuronidation in AML cells or impaired drug entry/retention in the AML cells. There may be additional forms of ribavirin resistance displayed by cancer cells. In HPV related oropharyngeal cancers, ribavirin reduced levels of phosphorylated form of eIF4E in some patients. The best response here was stable disease but another head and neck study had more promising results. For chronic hepatitis C, the oral (capsule or tablet) form of ribavirin is used only in combination with pegylated interferon alfa . Statins may improve this combination's efficacy in treating hepatitis C. When possible, genotyping of the specific viral strain is done; ribavirin is only used as a dose-escalating [lower-alpha 1] adjuvant to specific combinations of genotypes and other medications. Acute hepatitis C infection (within the first 6 months) often does not require immediate treatment, as many infections eventually resolve without treatment. When the decision is made to treat acute hepatitis C, ribavirin may be used as an adjunct to several drug combinations. However, other medications are preferred. Ribavirin is the only known treatment for a variety of viral hemorrhagic fevers , including Lassa fever , Crimean-Congo hemorrhagic fever , Venezuelan hemorrhagic fever , and Hantavirus infection, although data regarding these infections are scarce and the drug might be effective only in early stages. It is noted by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) that "Ribavirin has poor in vitro and in vivo activity against the filoviruses ( Ebola and Marburg ) and the flaviviruses ( dengue , yellow fever , Omsk hemorrhagic fever , and Kyasanur forest disease )" The aerosol form has been used in the past to treat respiratory syncytial virus -related diseases in children, although the evidence to support this is rather weak. Despite questions surrounding its efficacy, ribavirin remains the only antiviral known to be effective in treating Lassa fever. It has been used (in combination with ketamine , midazolam , and amantadine ) in treatment of rabies . Experimental data indicate that ribavirin may have useful activity against canine distemper and poxviruses . Ribavirin has also been used as a treatment for herpes simplex virus . One small study found that ribavirin treatment reduced the severity of herpes outbreaks and promoted recovery, as compared with placebo treatment. Another study found that ribavirin potentiated the antiviral effect of acyclovir . Some interest has been seen in its possible use as a treatment for cancers with elevated eukaryotic translation initiation factor eIF4E, especially acute myeloid leukemia (AML) as well as in head and neck cancers. Ribavirin targeted eIF4E in AML patients in monotherapy and combination studies and this corresponded to objective clinical responses including complete remissions. Ribavirin resistance in AML patients arose leading to loss of eIF4E targeting and relapse. Resistance was caused by deactivation of ribavirin through its glucuronidation in AML cells or impaired drug entry/retention in the AML cells. There may be additional forms of ribavirin resistance displayed by cancer cells. In HPV related oropharyngeal cancers, ribavirin reduced levels of phosphorylated form of eIF4E in some patients. The best response here was stable disease but another head and neck study had more promising results. The medication has two FDA "black box" warnings: One raises concerns that use before or during pregnancy by either sex may result in birth defects in the baby, and the other is regarding the risk of red blood cell breakdown. Ribavirin should not be given with zidovudine because of the increased risk of anemia; concurrent use with didanosine should likewise be avoided because of an increased risk of mitochondrial toxicity . It is a guanosine (ribonucleic) analog used to stop viral RNA synthesis and viral mRNA capping, thus, it is a nucleoside analog. Ribavirin is a prodrug , which when metabolized resembles purine RNA nucleotides . In this form, it interferes with RNA metabolism required for viral replication. Over five direct and indirect mechanisms have been proposed for its mechanism of action. The enzyme inosine triphosphate pyrophosphatase (ITPase) dephosphorylates ribavirin triphosphate in vitro to ribavirin monophosphate, and ITPase reduced enzymatic activity present in 30% of humans potentiates mutagenesis in hepatitis C virus. Ribavirin's amide group can make the native nucleoside drug resemble adenosine or guanosine, depending on its rotation. For this reason, when ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine , inducing mutations in RNA-dependent replication in RNA viruses. Such hypermutation can be lethal to RNA viruses. Neither of these mechanisms explains ribavirin's effect on many DNA viruses, which is more of a mystery, especially given the complete inactivity of ribavirin's 2' deoxyribose analogue, which suggests that the drug functions only as an RNA nucleoside mimic, and never a DNA nucleoside mimic. Ribavirin 5'-monophosphate inhibits cellular inosine monophosphate dehydrogenase , thereby depleting intracellular pools of GTP. [ failed verification ]Ribavirin's amide group can make the native nucleoside drug resemble adenosine or guanosine, depending on its rotation. For this reason, when ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine , inducing mutations in RNA-dependent replication in RNA viruses. Such hypermutation can be lethal to RNA viruses. Neither of these mechanisms explains ribavirin's effect on many DNA viruses, which is more of a mystery, especially given the complete inactivity of ribavirin's 2' deoxyribose analogue, which suggests that the drug functions only as an RNA nucleoside mimic, and never a DNA nucleoside mimic. Ribavirin 5'-monophosphate inhibits cellular inosine monophosphate dehydrogenase , thereby depleting intracellular pools of GTP. [ failed verification ]The eukaryotic translation initiation factor eIF4E plays multiple roles in RNA metabolism with translation being the best described. Biophysical and NMR studies first revealed that ribavirin directly bound the eIF4E,  providing another mechanism for its action. 3 H Ribavirin also interacts with eIF4E in cells. While inosine monophosphate dehydrogenase (IMPDH) presumably only binds the ribavirin monophosphate metabolite (RMP), eIF4E can bind ribavirin and with higher affinity ribavirin's phosphorylated forms. In many cell lines, studies into steady state levels of metabolites indicate that ribavirin triphosphate (RTP) is more abundant than the RMP metabolite which is the IMPDH ligand. RTP binds to eIF4E in its cap-binding site as observed by NMR. Ribavirin inhibits eIF4E activities in cells including in its RNA export, translation and oncogenic activities lines. In AML patients treated with ribavirin, ribavirin blocked the nuclear import of eIF4E through interfering with its interaction with its nuclear importer, Importin 8, thereby impairing its nuclear activities. Clinical relapse in AML patients corresponded to loss of ribavirin binding leading to nuclear re-entry of eIF4E and re-emergence of its nuclear activities. Ribavirin was first made in 1972 under the national cancer institute's Virus-Cancer program. This was done by researchers from International Chemical and Nuclear Corporation including Roberts A. Smith, Joseph T. Witkovski and Roland K. Robins. It was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity in the context of cancer chemotherapies. By the late 1970s, the Virus-Cancer program was widely considered a failure, and the drug development was abandoned. [ citation needed ] After the US Government announced that AIDS was caused by a retrovirus in 1984, drugs examined during the Virus-Cancer program and its focus on retroviruses were re-examined. Although the FDA first approved ribavirin as an antiviral in 1986, it was not indicated to treat HIV or AIDS. As a result, many people with AIDS sought to obtain black market ribavirin via buyer's clubs . The drug was approved for investigational use against hantavirus in the United States in 1993, but the results from a non-randomized uncontrolled trial were not encouraging: 71% of recipients became anemic and 47% died. In 2002 with the SARS outbreak , early speculation focused on Ribavirin as a possible anti-SARS agent. Early protocols adopted in Hong Kong adopted a "Hit Hard Hit Early" approach treating SARS with high doses of off-label steroids and Ribavirin. Unfortunately, it later turned out this haphazard approach was at best ineffective and at worst fatal, with many deaths attributed to SARS caused by ribavirin toxicity. Ribavirin is the INN and USAN , whereas tribavirin is the BAN . Brand names of generic forms include Copegus, Ribasphere, Rebetol. Ribavirin is the INN and USAN , whereas tribavirin is the BAN . Brand names of generic forms include Copegus, Ribasphere, Rebetol. Ribavirin is possibly best viewed as a ribosyl purine analogue with an incomplete purine 6-membered ring. This structural resemblance historically prompted replacement of the 2' nitrogen of the triazole with a carbon (which becomes the 5' carbon in an imidazole ), in an attempt to partly "fill out" the second ring--- but to no great effect. Such 5' imidazole riboside derivatives show antiviral activity with 5' hydrogen or halide, but the larger the substituent, the smaller the activity, and all proved less active than ribavirin. Note that two natural products were already known with this imidazole riboside structure: substitution at the 5' carbon with OH results in pyrazofurin , an antibiotic with antiviral properties but unacceptable toxicity, and replacement with an amino group results in the natural purine synthetic precursor 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside ( AICAR ), which has only modest antiviral properties. [ citation needed ] The most successful ribavirin derivative to date is the 3-carboxamidine derivative of the parent 3-carboxamide, first reported in 1973 by J. T. Witkowski et al., and now called taribavirin (former names "viramidine" and "ribamidine"). This drug shows a similar spectrum of antiviral activity to ribavirin, which is not surprising as it is now known to be a pro-drug for ribavirin. Taribavirin, however, has useful properties of less erythrocyte-trapping and better liver-targeting than ribavirin. The first property is due to taribavirin's basic amidine group which inhibits drug entry into RBCs, and the second property is probably due to increased concentration of the enzymes which convert amidine to amide in liver tissue. Taribavirin completed phase III human trials in 2012. The most successful ribavirin derivative to date is the 3-carboxamidine derivative of the parent 3-carboxamide, first reported in 1973 by J. T. Witkowski et al., and now called taribavirin (former names "viramidine" and "ribamidine"). This drug shows a similar spectrum of antiviral activity to ribavirin, which is not surprising as it is now known to be a pro-drug for ribavirin. Taribavirin, however, has useful properties of less erythrocyte-trapping and better liver-targeting than ribavirin. The first property is due to taribavirin's basic amidine group which inhibits drug entry into RBCs, and the second property is probably due to increased concentration of the enzymes which convert amidine to amide in liver tissue. Taribavirin completed phase III human trials in 2012.

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Crimean-Congo haemorrhagic fever

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Argentine hemorrhagic fever

Argentine hemorrhagic fever (AHF) or O'Higgins disease , also known in Argentina as mal de los rastrojos (stubble disease) is a hemorrhagic fever and zoonotic infectious disease occurring in Argentina. It is caused by the Junín virus (an arenavirus , closely related to the Machupo virus , causative agent of Bolivian hemorrhagic fever ). Its reservoir of infection is the drylands vesper mouse , a rodent found in Argentina and Paraguay.The disease was first reported in the town of O'Higgins [ es ] in Buenos Aires province, Argentina in 1958, giving it one of the names by which it is known. Theories about its nature included: Weil's disease , leptospirosis , chemical pollution. It was associated with fields containing stubble after the harvest, giving it another of its names. The endemic area of AHF covers approximately 150,000 km 2 , compromising the provinces of Buenos Aires , Córdoba , Santa Fe and La Pampa , with an estimated risk population of 5 million. [ citation needed ] The natural reservoir of infection, a small rodent known locally as ratón maicero ("maize mouse"; Calomys musculinus ), has chronic asymptomatic infection, and spreads the virus through its saliva and urine . Infection is produced through contact of skin or mucous membranes, or through inhalation of infected particles. It is found mostly in people who reside or work in rural areas; 80% of those infected are males between 15 and 60 years of age. [ citation needed ]AHF is a grave acute disease which may progress to recovery or death in 1 to 2 weeks. The incubation time of the disease is between 10 and 12 days, after which the first symptoms appear: fever, headaches, weakness, loss of appetite and will. These intensify less than a week later, forcing the infected to lie down, and producing stronger symptoms such as vascular, renal, hematological and neurological alterations. This stage lasts about 3 weeks. [ citation needed ] If untreated, the mortality of AHF reaches 15–30%. The specific treatment includes plasma of recovered patients, which, if started early, is extremely effective and reduces mortality to 1%. Ribavirin also has shown some promise in treating arenaviral diseases. The disease was first detected in the 1950s in the Junín Partido in Buenos Aires, after which its agent, the Junín virus, was named upon its identification in 1958. In the early years, about 1,000 cases per year were recorded, with a high mortality rate (more than 30%). The initial introduction of treatment serums in the 1970s reduced this lethality. The Candid #1 vaccine for AHF was created in 1985 by Argentine virologist Dr. Julio Barrera Oro. The vaccine was manufactured by the Salk Institute in the United States, and became available in Argentina in 1990. Antibodies produced by Candid #1 vaccination have also demonstrated cross-reactivity with Machupo virus in Rhesus macaques, and thus Candid #1 been considered for prophylactic use against Bolivian hemorrhagic fever . Candid #1 has been applied to adult high-risk population and is 95.5% effective. Between 1991 and 2005 more than 240,000 people were vaccinated, achieving a great decrease in the numbers of reported cases (94 suspect and 19 confirmed in 2005). On 29 August 2006 the Maiztegui Institute obtained certification for the production of the vaccine in Argentina. The vaccine produced in Argentina was found to be of similar effectiveness to the US vaccine. Details of the vaccine were published in 2011, and a protocol for production of the vaccine was published in 2018. Demand for the vaccine is insufficient to be commercially appealing due to the small target population, and it is considered an orphan drug ; the Argentine government committed itself to manufacture and sponsor Candid #1 vaccine. The Candid #1 vaccine for AHF was created in 1985 by Argentine virologist Dr. Julio Barrera Oro. The vaccine was manufactured by the Salk Institute in the United States, and became available in Argentina in 1990. Antibodies produced by Candid #1 vaccination have also demonstrated cross-reactivity with Machupo virus in Rhesus macaques, and thus Candid #1 been considered for prophylactic use against Bolivian hemorrhagic fever . Candid #1 has been applied to adult high-risk population and is 95.5% effective. Between 1991 and 2005 more than 240,000 people were vaccinated, achieving a great decrease in the numbers of reported cases (94 suspect and 19 confirmed in 2005). On 29 August 2006 the Maiztegui Institute obtained certification for the production of the vaccine in Argentina. The vaccine produced in Argentina was found to be of similar effectiveness to the US vaccine. Details of the vaccine were published in 2011, and a protocol for production of the vaccine was published in 2018. Demand for the vaccine is insufficient to be commercially appealing due to the small target population, and it is considered an orphan drug ; the Argentine government committed itself to manufacture and sponsor Candid #1 vaccine. Argentine hemorrhagic fever was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program. The Soviet Union also conducted research and developing programs on the potential of the hemorragic fever as a biological weapon.

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Crimean-Congo haemorrhagic fever

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List of abbreviations for diseases and disorders

This list contains acronyms and initials related to diseases (infectious or non-infectious) and medical disorders.

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Crimean-Congo haemorrhagic fever

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Milan Panić

Milan Panić ( Serbian Cyrillic : Милан Панић , pronounced [ mǐlan pǎːnit͡ɕ ] ; born 20 December 1929) is a Serbian-American businessman, humanitarian and former politician. He served as the Prime Minister of the Federal Republic of Yugoslavia from 1992 to 1993. During and after his time as prime minister, he campaigned for peace and democracy in the Balkan region. He ran for President of Serbia in 1992 , ultimately coming in second to Slobodan Milošević in an election marked by allegations of media and vote tampering by the ruling party. Panić became Prime Minister of Yugoslavia while an American citizen. The legality of retaining US citizenship while accepting this office has been questioned based on a Constitutional prohibition of a US citizen accepting office on behalf of a foreign nation. Panić is the first US citizen to occupy a high-level political position in a foreign country since Golda Meir . Panić is also the first civilian to serve as Defence Minister in the history of Serbia. Outside of his political and humanitarian activities, Panić built a lengthy career in the pharmaceutical and medical industries. He grew ICN Pharmaceuticals from a small operation in his garage into a global pharmaceutical corporation listed on the New York Stock Exchange , with over $672 million in annual sales across 90 countries at its peak. After retiring from ICN, he spun off an ICN subsidiary and renamed it MP Biomedicals. The company is a global producer of life science and diagnostic products, with operations in North America, Asia, Australia, and Europe. In October 2015, Panić announced the pending sale of MP Biomedicals to a Chinese chemical company, Valiant Fine Chemicals Co., Ltd. Panić pursues philanthropy personally and through his Milan Panić Jr. Foundation, as well as MP Global Enterprises & Associates, LLC. As part of his philanthropic efforts, he has sponsored scholarships at the MIT - Harvard Medical School Program and lectured on peacebuilding at George Washington University and University of Southern California . He is also a member of the President's cabinet at Chapman University , Vice Chairman and sponsor of the Los Angeles Opera , and frequent sponsor of California cultural institutions and charities.Panić was born on 20 December 1929 in Belgrade , Kingdom of Yugoslavia (present-day Serbia) into a middle-class family. His father, a prominent government official, died when he was three years old, leaving Panić's mother to raise him and his sisters. Faced with a growing shortage of goods due to the Nazi occupation of Belgrade, Panić started a working vegetable farm to support his family and community. As a young student, he gravitated toward geography and chemistry, assembling a small laboratory in his room to conduct experiments. During World War II, Panić, then only 14 years old, joined Josip "Marshal" Tito 's partisan resistance to fight the growing Nazi influence in Yugoslavia. After returning from military service, he resumed his secondary studies in biochemistry at the Belgrade Faculty of Technology. Panić enrolled as a medical student at the University of Belgrade medical school before transferring to the biochemistry degree program. Panić was an avid cyclist from his youth into early adulthood. Over the course of his cycling career, he eventually rose to become a Yugoslavian national champion and competed at the international level on prominent teams including the Yugoslavian national and Olympic teams. While traveling to an international cycling tournament in the Netherlands in 1955, Panić defected to Austria with his wife Jelica Panić ( née Narandžić.) After defecting to Austria in August 1955, Panić and his wife applied for asylum in Germany and moved to a West German refugee camp. While in Germany, he enrolled in the PhD program at the University of Heidelberg and worked as a furniture mover. After receiving asylum in Germany several months after his initial arrival, Panić applied for a program that resettled refugees in the United States . Upon their acceptance into the program, he and Jelica moved to Fontana, California in early 1956. Panić worked in labs at Kaiser Steel and the University of Southern California , where he also studied biochemistry. In 1959, Panić decided to start his own business, the International Chemical and Nuclear Corporation (ICN). [ citation needed ]Panić was born on 20 December 1929 in Belgrade , Kingdom of Yugoslavia (present-day Serbia) into a middle-class family. His father, a prominent government official, died when he was three years old, leaving Panić's mother to raise him and his sisters. Faced with a growing shortage of goods due to the Nazi occupation of Belgrade, Panić started a working vegetable farm to support his family and community. As a young student, he gravitated toward geography and chemistry, assembling a small laboratory in his room to conduct experiments. During World War II, Panić, then only 14 years old, joined Josip "Marshal" Tito 's partisan resistance to fight the growing Nazi influence in Yugoslavia. After returning from military service, he resumed his secondary studies in biochemistry at the Belgrade Faculty of Technology. Panić enrolled as a medical student at the University of Belgrade medical school before transferring to the biochemistry degree program. Panić was an avid cyclist from his youth into early adulthood. Over the course of his cycling career, he eventually rose to become a Yugoslavian national champion and competed at the international level on prominent teams including the Yugoslavian national and Olympic teams. While traveling to an international cycling tournament in the Netherlands in 1955, Panić defected to Austria with his wife Jelica Panić ( née Narandžić.) After defecting to Austria in August 1955, Panić and his wife applied for asylum in Germany and moved to a West German refugee camp. While in Germany, he enrolled in the PhD program at the University of Heidelberg and worked as a furniture mover. After receiving asylum in Germany several months after his initial arrival, Panić applied for a program that resettled refugees in the United States . Upon their acceptance into the program, he and Jelica moved to Fontana, California in early 1956. Panić worked in labs at Kaiser Steel and the University of Southern California , where he also studied biochemistry. In 1959, Panić decided to start his own business, the International Chemical and Nuclear Corporation (ICN). [ citation needed ]In July 1992, Panić assumed the position of Prime Minister of the Federal Republic of Yugoslavia, at the request of Yugoslav President Dobrica Ćosić and Serbian President Slobodan Milošević. Panić set out goals of achieving peace, drafting a constitution, lifting U.N. sanctions, and pushing for the closure of concentration camps. In August 1992, he played a central role in the London International Conference on the Former Yugoslavia, which called for international attention to the country's worsening economic and political situation. At the conference, Panić submitted a twelve-point Plan for Peace. One month later, Panić delivered a "Speech of Peace" address in front of the United Nations General Assembly . On 2 December 1992, Panić announced his intention to challenge Milošević for the Serbian presidency, campaigning on a platform of economic reforms and bringing a peaceful resolution to the Bosnian War . Panić contended that Milošević had crippled Serbia by allowing unemployment and inflation to rise, while inciting isolation and sanctions by the international community. Panić appealed directly to Serbian youth and older voters seeking a compromise in the ongoing conflict that included recognition of Croatia and Bosnia-Herzegovina in their current borders. In the 1992 Serbian general election , Panić came in second behind Milošević, receiving 32% of votes cast. In the aftermath, observers at the Helsinki Commission, political experts, and journalists alleged that Milošević and his supporters had manipulated the election results through improper use of state media and vote tampering. Following his term as prime minister, Panić stayed involved in the effort to restore peace and democracy in the region. In December 1993, he began correspondence with U.S. President Bill Clinton regarding a proposed peace summit with all heads of state of the former Yugoslavia. In 1994, he met with Clinton and his advisers in California to discuss the proposal further. Following additional discussions over the next two years, in which Panić proposed a Balkans peace conference, the Clinton Administration convened the Conference on Establishing Peace at Wright-Patterson Air Force Base in Dayton, Ohio, USA. The Conference culminated in the signing of the Dayton Accords on 21 November 1995, which brought an end to the Bosnian War by dividing Bosnia and Herzegovina into two separate entities: The Federation of Bosnia and Herzegovina and the Republika Srpska . Since the end of the war, Panić has continued to push for democracy in the Yugoslav region by convening political activists and advocating in the media. In July 1992, Panić assumed the position of Prime Minister of the Federal Republic of Yugoslavia, at the request of Yugoslav President Dobrica Ćosić and Serbian President Slobodan Milošević. Panić set out goals of achieving peace, drafting a constitution, lifting U.N. sanctions, and pushing for the closure of concentration camps. In August 1992, he played a central role in the London International Conference on the Former Yugoslavia, which called for international attention to the country's worsening economic and political situation. At the conference, Panić submitted a twelve-point Plan for Peace. One month later, Panić delivered a "Speech of Peace" address in front of the United Nations General Assembly . On 2 December 1992, Panić announced his intention to challenge Milošević for the Serbian presidency, campaigning on a platform of economic reforms and bringing a peaceful resolution to the Bosnian War . Panić contended that Milošević had crippled Serbia by allowing unemployment and inflation to rise, while inciting isolation and sanctions by the international community. Panić appealed directly to Serbian youth and older voters seeking a compromise in the ongoing conflict that included recognition of Croatia and Bosnia-Herzegovina in their current borders. In the 1992 Serbian general election , Panić came in second behind Milošević, receiving 32% of votes cast. In the aftermath, observers at the Helsinki Commission, political experts, and journalists alleged that Milošević and his supporters had manipulated the election results through improper use of state media and vote tampering. Following his term as prime minister, Panić stayed involved in the effort to restore peace and democracy in the region. In December 1993, he began correspondence with U.S. President Bill Clinton regarding a proposed peace summit with all heads of state of the former Yugoslavia. In 1994, he met with Clinton and his advisers in California to discuss the proposal further. Following additional discussions over the next two years, in which Panić proposed a Balkans peace conference, the Clinton Administration convened the Conference on Establishing Peace at Wright-Patterson Air Force Base in Dayton, Ohio, USA. The Conference culminated in the signing of the Dayton Accords on 21 November 1995, which brought an end to the Bosnian War by dividing Bosnia and Herzegovina into two separate entities: The Federation of Bosnia and Herzegovina and the Republika Srpska . Since the end of the war, Panić has continued to push for democracy in the Yugoslav region by convening political activists and advocating in the media. In 1959, Panić launched ICN out of his garage just outside of Los Angeles , CA using $200 in startup capital. His initial business model was built upon synthesizing chemical compounds to sell to California research labs. During the 1960s, ICN marketed a generic version of L-Dopa , a widely used Parkinson's disease antidote. Panić led ICN over the following decades to develop the building blocks for several thousand potential new drugs. As ICN grew, Panić moved his operations from Pasadena, CA to a new research lab in Costa Mesa, CA and renamed the company ICN Pharmaceuticals. In 1967, ICN was officially listed on the New York Stock Exchange . In 1972, ICN discovered the ribavirin compound, the earliest recorded broad spectrum antiviral agent. Chemists Joseph T. Witkovski and Ronald K. Robins were integral to the compound's creation. In 1985, ribavirin was approved under the name Virazole by the Food and Drug Administration for the treatment of respiratory syncytial virus (RSV), an upper respiratory tract disease that primarily affects children. In 1991, ICN created the SPAG-2 (Small Particle Aerosol Generator) nebulizer to administer an aerosolized form of ribavirin during hospital treatments of specific viral infections. In 1985, ICN and the Eastman-Kodak company launched a six-year, $45 million joint venture to research drugs that slow, halt, or reverse the aging process. Between 1986 and 1987, the FDA contended that ICN had exaggerated Virazole's effectiveness in treating other illnesses including the AIDS virus. ICN settled with the FDA in 1991. In January 1988, ICN acquired 7.3% of Swiss pharmaceutical company Hoffman-La Roche, as part of a reported acquisition strategy to expand ICN's reach and marketing capabilities. Following the fall of the Berlin Wall , ICN acquired multiple pharmaceutical firms in Eastern Europe. In May 1991, ICN bought 75% of Galenika , Yugoslavia's largest drug maker at the time. After eight months, the new subsidiary ICN-Galenika was producing revenues of $364 million. In April 1992, ICN Pharmaceuticals and ICN-Galenika partially financed a $100,000 initiative to vaccinate children in the Yugoslav province of Kosovo. In 1995, the Securities and Exchange Commission (SEC) investigated ICN over shareholder concerns related to Mr. Panić's sale of company stock before a key regulatory decision by the FDA. After a three-year investigation, the SEC dropped its inquiry in 1998 with no charges filed. In 1998, the FDA approved Virazole for the treatment of Hepatitis C in conjunction with another medication called interferon. Virazole eventually became a global standard treatment for multiple pediatric and adult medical conditions. Uses include the effective treatment of chronic Hepatitis C in conjunction with interferon, multiple viral fevers including influenza, parainfluenza, adenovirus, measles, Crimean-Congo hemorrhagic fever and Lassa fever, as well as renal impairment and thyroid cancer. During the 1990s, Panić resolved four sexual harassment suits filed by former employees of ICN. In 2002, ICN settled an SEC civil lawsuit related to misleading statements issued regarding their products. Panić decided to retire as CEO and Chairman of ICN in June 2002 after opposing shareholders took control of ICN's Board of Directors. Over the course of his career as Chairman, CEO, and President, Panić led ICN to annual sales in 90 countries exceeding $672 million (USD), with over 600 drugs in its portfolio by his final year in 2001. Panić maintains other business entities and investments both in the U.S. and internationally. In 2003, after Panić's departure, ICN Pharmaceuticals changed its name to Valeant Pharmaceuticals International, Inc . After retiring from ICN, Panić bought a bioassay subsidiary of ICN Biomedicals and changed its name to MP Biomedicals. MP specializes in research and development of life science and diagnostic products. MP's global headquarters is located in Santa Ana, California, with its US headquarters and central distribution center located in Solon, Ohio . The company maintains global operations in North America, South America, Asia, Australia, and Europe. On 14 June 2010, Panić and MP acquired ICPBio International LTD., a New Zealand-based protein biologics manufacturing company. On 11 December 2014, the FDA approved MP Diagnostics HTLV Blot 2.4, the first FDA-licensed supplemental test for Human T-cell Lymphotropic Virus-I/II (HTLV-I/II). In October 2015, Panić announced the sale of MP Biomedicals to China-based Valiant Fine Chemicals Co. Ltd., a developer of chemical products. In 1959, Panić launched ICN out of his garage just outside of Los Angeles , CA using $200 in startup capital. His initial business model was built upon synthesizing chemical compounds to sell to California research labs. During the 1960s, ICN marketed a generic version of L-Dopa , a widely used Parkinson's disease antidote. Panić led ICN over the following decades to develop the building blocks for several thousand potential new drugs. As ICN grew, Panić moved his operations from Pasadena, CA to a new research lab in Costa Mesa, CA and renamed the company ICN Pharmaceuticals. In 1967, ICN was officially listed on the New York Stock Exchange . In 1972, ICN discovered the ribavirin compound, the earliest recorded broad spectrum antiviral agent. Chemists Joseph T. Witkovski and Ronald K. Robins were integral to the compound's creation. In 1985, ribavirin was approved under the name Virazole by the Food and Drug Administration for the treatment of respiratory syncytial virus (RSV), an upper respiratory tract disease that primarily affects children. In 1991, ICN created the SPAG-2 (Small Particle Aerosol Generator) nebulizer to administer an aerosolized form of ribavirin during hospital treatments of specific viral infections. In 1985, ICN and the Eastman-Kodak company launched a six-year, $45 million joint venture to research drugs that slow, halt, or reverse the aging process. Between 1986 and 1987, the FDA contended that ICN had exaggerated Virazole's effectiveness in treating other illnesses including the AIDS virus. ICN settled with the FDA in 1991. In January 1988, ICN acquired 7.3% of Swiss pharmaceutical company Hoffman-La Roche, as part of a reported acquisition strategy to expand ICN's reach and marketing capabilities. Following the fall of the Berlin Wall , ICN acquired multiple pharmaceutical firms in Eastern Europe. In May 1991, ICN bought 75% of Galenika , Yugoslavia's largest drug maker at the time. After eight months, the new subsidiary ICN-Galenika was producing revenues of $364 million. In April 1992, ICN Pharmaceuticals and ICN-Galenika partially financed a $100,000 initiative to vaccinate children in the Yugoslav province of Kosovo. In 1995, the Securities and Exchange Commission (SEC) investigated ICN over shareholder concerns related to Mr. Panić's sale of company stock before a key regulatory decision by the FDA. After a three-year investigation, the SEC dropped its inquiry in 1998 with no charges filed. In 1998, the FDA approved Virazole for the treatment of Hepatitis C in conjunction with another medication called interferon. Virazole eventually became a global standard treatment for multiple pediatric and adult medical conditions. Uses include the effective treatment of chronic Hepatitis C in conjunction with interferon, multiple viral fevers including influenza, parainfluenza, adenovirus, measles, Crimean-Congo hemorrhagic fever and Lassa fever, as well as renal impairment and thyroid cancer. During the 1990s, Panić resolved four sexual harassment suits filed by former employees of ICN. In 2002, ICN settled an SEC civil lawsuit related to misleading statements issued regarding their products. Panić decided to retire as CEO and Chairman of ICN in June 2002 after opposing shareholders took control of ICN's Board of Directors. Over the course of his career as Chairman, CEO, and President, Panić led ICN to annual sales in 90 countries exceeding $672 million (USD), with over 600 drugs in its portfolio by his final year in 2001. Panić maintains other business entities and investments both in the U.S. and internationally. In 2003, after Panić's departure, ICN Pharmaceuticals changed its name to Valeant Pharmaceuticals International, Inc . After retiring from ICN, Panić bought a bioassay subsidiary of ICN Biomedicals and changed its name to MP Biomedicals. MP specializes in research and development of life science and diagnostic products. MP's global headquarters is located in Santa Ana, California, with its US headquarters and central distribution center located in Solon, Ohio . The company maintains global operations in North America, South America, Asia, Australia, and Europe. On 14 June 2010, Panić and MP acquired ICPBio International LTD., a New Zealand-based protein biologics manufacturing company. On 11 December 2014, the FDA approved MP Diagnostics HTLV Blot 2.4, the first FDA-licensed supplemental test for Human T-cell Lymphotropic Virus-I/II (HTLV-I/II). In October 2015, Panić announced the sale of MP Biomedicals to China-based Valiant Fine Chemicals Co. Ltd., a developer of chemical products. Panić provides philanthropic support to various universities, research programs, museums, political causes and charities through both his Milan Panić Jr. Foundation and MP Global Enterprises & Associates, LLC. As part of his philanthropic efforts, he has supported the Muscular Dystrophy Association and sponsored scholarships at the MIT-Harvard Medical School Program. Panić has lectured frequently on peacebuilding at George Washington University, University of Southern California, and Chapman University - where he is a member of the President's cabinet. Panić has provided support to the Freedoms Foundation in Valley Forge, PA, penning the Bill of Responsibilities and donating a Bill of Responsibilities Monument to their headquarters in 1990. He is a frequent supporter of California cultural institutions including the Los Angeles Opera, where he serves as a Vice Chairman and has sponsored season-opening performances since 2002. He has also provided charitable support to City of Hope Cancer Research and Treatment Center. Panić was married to mezzo-soprano opera singer Milena Kitic before the couple divorced; together they had a son. Panić was awarded the Ellis Island Medal of Honor by the Statue of Liberty-Ellis Island Foundation on 27 October 1986. He was named "European of the Year" in 1992 by the Wall Street Journal Europe , which cited his efforts while serving Yugoslavian Prime Minister to introduce democratic, free market reforms, bring peace, and galvanize opposition to Slobodan Milošević. Panić was presented the Chamber Global Award by the Chamber of Commerce Belgium-Luxembourg South-Eastern Europe in Brussels on 17 December 2002. In February 2015, the Lifeline Humanitarian Organization of New York awarded Panić with a lifetime achievement award for his philanthropic support of academic, cultural, political, and relief organizations around the world. Prime Minister for Peace: My Struggle for Serbian Democracy. With Kevin C. Murphy. Lanham, MD: Rowman and Littlefield., 2015.

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Crimean-Congo haemorrhagic fever

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Rift Valley fever

Rift Valley fever ( RVF ) is a viral disease of humans and livestock that can cause mild to severe symptoms. The mild symptoms may include: fever , muscle pains , and headaches which often last for up to a week. The severe symptoms may include: loss of sight beginning three weeks after the infection, infections of the brain causing severe headaches and confusion , and bleeding together with liver problems which may occur within the first few days. Those who have bleeding have a chance of death as high as 50%. The disease is caused by the RVF virus . It is spread by either touching infected animal blood, breathing in the air around an infected animal being butchered , drinking raw milk from an infected animal, or the bite of infected mosquitoes . Animals such as cows, sheep, goats, and camels may be affected. In these animals it is spread mostly by mosquitoes. It does not appear that one person can infect another person. The disease is diagnosed by finding antibodies against the virus or the virus itself in the blood. Prevention of the disease in humans is accomplished by vaccinating animals against the disease. This must be done before an outbreak occurs because if it is done during an outbreak it may worsen the situation. Stopping the movement of animals during an outbreak may also be useful, as may decreasing mosquito numbers and avoiding their bites. There is a human vaccine ; however, as of 2010 it is not widely available. There is no specific treatment and medical efforts are supportive. Outbreaks of the disease have only occurred in Africa and Arabia . Outbreaks usually occur during periods of increased rain which increase the number of mosquitoes. The disease was first reported among livestock in Rift Valley of Kenya in the early 1900s, and the virus was first isolated in 1931. In humans, the virus can cause several syndromes. Usually, they have either no symptoms or only a mild illness with fever, headache , muscle pains , and liver abnormalities. In a small percentage of cases (< 2%), the illness can progress to hemorrhagic fever syndrome, meningoencephalitis (inflammation of the brain and tissues lining the brain ), or affect the eye. Patients who become ill usually experience fever, generalised weakness, back pain, dizziness, and weight loss at the onset of the illness. Typically, people recover within two to seven days after onset. About 1% of people with the disease die of it. In livestock, the fatality level is significantly higher. Pregnant livestock infected with RVF abort virtually 100% of foetuses. An epizootic (animal disease epidemic) of RVF is usually first indicated by a wave of unexplained abortions. [ citation needed ] Other signs in livestock include vomiting and diarrhea, respiratory disease, fever, lethargy, anorexia and sudden death in young animals. The virus belongs to the Bunyavirales order. This is an order of enveloped negative single stranded RNA viruses. All Bunyaviruses have an outer lipid envelope with two glycoproteins —G(N) and G(C)—required for cell entry. They deliver their genome into the host-cell cytoplasm by fusing their envelope with an endosomal membrane . [ citation needed ] The virus' G(C) protein has a class II membrane fusion protein architecture similar to that found in flaviviruses and alphaviruses . This structural similarity suggests that there may be a common origin for these viral families. [ citation needed ] The virus' 11.5 kb tripartite genome is composed of single-stranded RNA . As a Phlebovirus , it has an ambisense genome. Its L and M segments are negative-sense, but its S segment is ambisense. These three genome segments code for six major proteins: L protein ( viral polymerase ), the two glycoproteins G(N) and G(C), the nucleocapsid N protein, and the nonstructural NSs and NSm proteins. The virus is transmitted through mosquito vectors , as well as through contact with the tissue of infected animals. Two species— Culex tritaeniorhynchus and Aedes vexans —are known to transmit the virus. Other potential vectors include Aedes caspius , Aedes mcintosh , Aedes ochraceus , Culex pipiens , Culex antennatus , Culex perexiguus , Culex zombaensis and Culex quinquefasciatus . Contact with infected tissue is considered to be the main source of human infections. The virus has been isolated from two bat species: the Peter's epauletted fruit bat ( Micropteropus pusillus ) and the aba roundleaf bat ( Hipposideros abae ), which are believed to be reservoirs for the virus. The virus belongs to the Bunyavirales order. This is an order of enveloped negative single stranded RNA viruses. All Bunyaviruses have an outer lipid envelope with two glycoproteins —G(N) and G(C)—required for cell entry. They deliver their genome into the host-cell cytoplasm by fusing their envelope with an endosomal membrane . [ citation needed ] The virus' G(C) protein has a class II membrane fusion protein architecture similar to that found in flaviviruses and alphaviruses . This structural similarity suggests that there may be a common origin for these viral families. [ citation needed ] The virus' 11.5 kb tripartite genome is composed of single-stranded RNA . As a Phlebovirus , it has an ambisense genome. Its L and M segments are negative-sense, but its S segment is ambisense. These three genome segments code for six major proteins: L protein ( viral polymerase ), the two glycoproteins G(N) and G(C), the nucleocapsid N protein, and the nonstructural NSs and NSm proteins. The virus is transmitted through mosquito vectors , as well as through contact with the tissue of infected animals. Two species— Culex tritaeniorhynchus and Aedes vexans —are known to transmit the virus. Other potential vectors include Aedes caspius , Aedes mcintosh , Aedes ochraceus , Culex pipiens , Culex antennatus , Culex perexiguus , Culex zombaensis and Culex quinquefasciatus . Contact with infected tissue is considered to be the main source of human infections. The virus has been isolated from two bat species: the Peter's epauletted fruit bat ( Micropteropus pusillus ) and the aba roundleaf bat ( Hipposideros abae ), which are believed to be reservoirs for the virus. Although many components of the RVFV's RNA play an important role in the virus' pathology, the nonstructural protein encoded on the S segment (NSs) is the only component that has been found to directly affect the host. NSs is hostile and combative against the host interferon (IFNs) antiviral response. IFNs are essential in order for the immune system to fight off viral infections in a host. This inhibitory mechanism is believed to be due to a number of reasons, the first being, competitive inhibition of the formation of the transcription factor. On this transcription factor, NSs interacts with and binds to a subunit that is needed for RNA polymerase I and II. This interaction cause competitive inhibition with another transcription factor component and prevents the assembly process of the transcription factor complex, which results in the suppression of the host antiviral response. Transcription suppression is believed to be another mechanism of this inhibitory process. This occurs when an area of NSs interacts with and binds to the host's protein, SAP30 and forms a complex. This complex causes histone acetylation to regress, which is needed for transcriptional activation of the IFN promoter. This causes IFN expression to be obstructed. Lastly, NSs has also been known to affect regular activity of double-stranded RNA-dependent protein kinase R. This protein is involved in cellular antiviral responses in the host. When RVFV is able to enter the host's DNA, NSs forms a filamentous structure in the nucleus. This allows the virus to interact with specific areas of the host's DNA that relates to segregation defects and induction of chromosome continuity. This increases host infectivity and decreases the host's antiviral response. Diagnosis relies on viral isolation from tissues, or serological testing with an ELISA . Other methods of diagnosis include Nucleic Acid Testing (NAT), cell culture , and IgM antibody assays. As of September 2016, the Kenya Medical Research Institute (KEMRI) has developed a product called Immunoline, designed to diagnose the disease in humans much faster than in previous methods. A person's chances of becoming infected can be reduced by taking measures to decrease contact with blood, body fluids, or tissues of infected animals and protection against mosquitoes and other bloodsucking insects. Use of mosquito repellents and bed nets are two effective methods. For persons working with animals in RVF-endemic areas, wearing protective equipment to avoid any exposure to blood or tissues of animals that may potentially be infected is an important protective measure. Potentially, establishing environmental monitoring and case surveillance systems may aid in the prediction and control of future RVF outbreaks. No vaccines are currently available for humans. While a vaccines have been developed for humans, it has only been used experimentally for scientific personnel in high-risk environments. Trials of a number of vaccines, such as NDBR-103 and TSI-GSD 200, are ongoing. Different types of vaccines for veterinary use are available. The killed vaccines are not practical in routine animal field vaccination because of the need of multiple injections. Live vaccines require a single injection but are known to cause birth defects and abortions in sheep and induce only low-level protection in cattle. The live-attenuated vaccine, MP-12, has demonstrated promising results in laboratory trials in domesticated animals, but more research is needed before the vaccine can be used in the field. The live-attenuated clone 13 vaccine was recently registered and used in South Africa. Alternative vaccines using molecular recombinant constructs are in development and show promising results. A vaccine has been conditionally approved for use in animals in the US. It has been shown that knockout of the NSs and NSm nonstructural proteins of this virus produces an effective vaccine in sheep as well. RVF outbreaks occur across sub-Saharan Africa , with outbreaks occurring elsewhere infrequently. Outbreaks of this disease usually correspond with the warm phases of the EI Niño/Southern Oscillation. During this time there is an increase in rainfall, flooding and greenness of vegetation index , which leads to an increase in mosquito vectors. RVFV can be transmitted vertically in mosquitos, meaning that the virus can be passed from the mother to her offspring. During dry conditions, the virus can remain viable for a number of years in the egg. Mosquitos lay their eggs in water, where they eventually hatch. As water is essential for mosquito eggs to hatch, rainfall and flooding cause an increase in the mosquito population and an increased potential for the virus. The first documented outbreak was identified in Kenya in 1931, in sheep, cattle and humans; another severe outbreak in the country in 1950–1951 involved 100,000 deaths in livestock and an unrecorded number of humans with fever. An outbreak occurred in South Africa in 1974–1976, with more than 500,000 infected animals and the first deaths in humans. In Egypt in 1977–78, an estimated 200,000 people were infected and there were at least 594 deaths. In Kenya in 1998, the virus killed more than 400 people. [ citation needed ] Since then, there have been outbreaks in Saudi Arabia and Yemen (2000), [ citation needed ] East Africa (2006–2007) , Sudan (2007), South Africa (2010), Uganda (2016), Kenya (2018), and Mayotte (2018–2019). 2020–2021 in Kenya, in 2022 an outbreak is ongoing in Burundi.Rift Valley fever was one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program in 1969. The disease is one of several identified by WHO as a likely cause of a future epidemic in a new plan developed after the Ebola epidemic for urgent research and development toward new diagnostic tests, vaccines and medicines.

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Crimean-Congo haemorrhagic fever

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Lassa fever

Lassa fever , also known as Lassa hemorrhagic fever , is a type of viral hemorrhagic fever caused by the Lassa virus . Many of those infected by the virus do not develop symptoms . When symptoms occur they typically include fever , weakness, headaches, vomiting , and muscle pains . Less commonly there may be bleeding from the mouth or gastrointestinal tract . The risk of death once infected is about one percent and frequently occurs within two weeks of the onset of symptoms. Of those who survive, about a quarter have hearing loss , which improves within three months in about half of these cases. The disease is usually initially spread to people via contact with the urine or feces of an infected multimammate mouse . Spread can then occur via direct contact between people. Diagnosis based on symptoms is difficult. Confirmation is by laboratory testing to detect the virus's RNA , antibodies for the virus, or the virus itself in cell culture . Other conditions that may present similarly include Ebola , malaria , typhoid fever , and yellow fever . The Lassa virus is a member of the Arenaviridae family of viruses . There is no vaccine . Prevention requires isolating those who are infected and decreasing contact with the mice. Other efforts to control the spread of disease include having a cat to hunt vermin , and storing food in sealed containers. Treatment is directed at addressing dehydration and improving symptoms. The antiviral medication ribavirin has been recommended, but evidence to support its use is weak. Descriptions of the disease date from the 1950s. The virus was first described in 1969 from a case in the town of Lassa, in Borno State , Nigeria . Lassa fever is relatively common in West Africa including the countries of Nigeria , Liberia , Sierra Leone , Guinea , and Ghana . There are about 300,000 to 500,000 cases which result in 5,000 deaths a year. Onset of symptoms is typically 7 to 21 days after exposure. In 80% of those who are infected few or no symptoms occur. These mild symptoms may include fever, tiredness, weakness, and headache. In 20% of people more severe symptoms such as bleeding gums, breathing problems, vomiting, chest pain, or dangerously low blood pressure may occur. Long term complications may include hearing loss . In those who are pregnant , miscarriage may occur in 95% of child-bearing females . Lassa fever can be difficult to distinguish clinically from other viral hemorrhagic fevers, such as Ebola virus disease . A combination of pharyngitis , pain behind the sternum , presence of excess protein in the urine and fever can indicate Lassa fever with higher specificity. In cases in which death occurs, this typically occurs within 14 days of onset. About 1% of all Lassa virus infections result in death. Approximately 15%-20% of those who have required hospitalization for Lassa fever die. The risk of death is greater in those who are pregnant. A "Swollen baby syndrome" may occur in newborns, infants and toddlers with pitting edema , abdominal distension and bleeding. Lassa virus is a member of the Arenaviridae , a family of negative-sense, single-stranded RNA viruses . Specifically it is an old world arenavirus, which is enveloped, single-stranded, and bi-segmented RNA. Lassa virus contains both a large and a small genome section, with seven lineages identified to date: Lineages I, II, and III from Nigeria ; Lineage IV from Sierra Leone , Guinea , and Liberia ; Lineage V from Cote D'Ivoire and Mali Lineage VI from Togo ; and Lineage VII from Benin . Lassa virus commonly spreads to humans from other animals, specifically the Natal multimammate mouse or African rat, also called the Natal multimammate rat ( Mastomys natalensis ). This is probably the most common mouse in equatorial Africa, common in human households and eaten as a delicacy in some areas. The multimammate mouse can quickly produce a large number of offspring, tends to colonize human settlements, increasing the risk of rodent-human contact, and is found throughout the west, central and eastern parts of the African continent. Once the mouse has become a carrier, it will excrete the virus throughout the rest of its lifetime through feces and urine creating ample opportunity for exposure. The virus is probably transmitted by contact with the feces or urine of animals accessing grain stores in residences. No study has proven presence in breast milk, but the high level of viremia suggests it may be possible. Individuals who are at a higher risk of contracting the infection are those who live in rural areas where Mastomys are discovered, and where sanitation is not prevalent. Infection typically occurs by direct or indirect exposure to animal excrement through the respiratory or gastrointestinal tracts. Inhalation of tiny particles of infectious material (aerosol) is believed to be the most significant means of exposure. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infectious material. Transmission from person to person has been established, presenting a disease risk for healthcare workers. The virus is present in urine for between three and nine weeks after infection, and it can be transmitted in semen for up to three months after becoming infected. Lassa virus is a member of the Arenaviridae , a family of negative-sense, single-stranded RNA viruses . Specifically it is an old world arenavirus, which is enveloped, single-stranded, and bi-segmented RNA. Lassa virus contains both a large and a small genome section, with seven lineages identified to date: Lineages I, II, and III from Nigeria ; Lineage IV from Sierra Leone , Guinea , and Liberia ; Lineage V from Cote D'Ivoire and Mali Lineage VI from Togo ; and Lineage VII from Benin . Lassa virus commonly spreads to humans from other animals, specifically the Natal multimammate mouse or African rat, also called the Natal multimammate rat ( Mastomys natalensis ). This is probably the most common mouse in equatorial Africa, common in human households and eaten as a delicacy in some areas. The multimammate mouse can quickly produce a large number of offspring, tends to colonize human settlements, increasing the risk of rodent-human contact, and is found throughout the west, central and eastern parts of the African continent. Once the mouse has become a carrier, it will excrete the virus throughout the rest of its lifetime through feces and urine creating ample opportunity for exposure. The virus is probably transmitted by contact with the feces or urine of animals accessing grain stores in residences. No study has proven presence in breast milk, but the high level of viremia suggests it may be possible. Individuals who are at a higher risk of contracting the infection are those who live in rural areas where Mastomys are discovered, and where sanitation is not prevalent. Infection typically occurs by direct or indirect exposure to animal excrement through the respiratory or gastrointestinal tracts. Inhalation of tiny particles of infectious material (aerosol) is believed to be the most significant means of exposure. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infectious material. Transmission from person to person has been established, presenting a disease risk for healthcare workers. The virus is present in urine for between three and nine weeks after infection, and it can be transmitted in semen for up to three months after becoming infected. A range of laboratory investigations are performed, where possible, to diagnose the disease and assess its course and complications. The confidence of a diagnosis can be compromised if laboratory tests are not available. One comprising factor is the number of febrile illnesses present in Africa, such as malaria or typhoid fever that could potentially exhibit similar symptoms, particularly for non-specific manifestations of Lassa fever. In cases with abdominal pain , in countries where Lassa is common, Lassa fever is often misdiagnosed as appendicitis and intussusception which delays treatment with the antiviral ribavirin . In West Africa, where Lassa is most common, it is difficult to diagnose due to the absence of proper equipment to perform testing. The FDA has yet to approve a widely validated laboratory test for Lassa, but there are tests that have been able to provide definitive proof of the presence of the LASV virus. These tests include cell cultures, PCR, ELISA antigen assays, plaque neutralization assays, and immunofluorescence essays. However, immunofluorescence essays provide less definitive proof of Lassa infection. An ELISA test for antigen and Immunoglobulin M antibodies give 88% sensitivity and 90% specificity for the presence of the infection. Other laboratory findings in Lassa fever include lymphocytopenia (low white blood cell count), thrombocytopenia (low platelets), and elevated aspartate transaminase levels in the blood. Lassa fever virus can also be found in cerebrospinal fluid . Control of the Mastomys rodent population is impractical, so measures focus on keeping rodents out of homes and food supplies, encouraging effective personal hygiene, storing grain and other foodstuffs in rodent-proof containers, and disposing of garbage far from the home to help sustain clean households. Gloves, masks, laboratory coats, and goggles are advised while in contact with an infected person, to avoid contact with blood and body fluids. These issues in many countries are monitored by a department of public health . In less developed countries, these types of organizations may not have the necessary means to effectively control outbreaks. There is no vaccine for humans as of 2023. Researchers at the United States Army Medical Research Institute of Infectious Diseases facility had a promising vaccine candidate in 2002. They have developed a replication -competent vaccine against Lassa virus based on recombinant vesicular stomatitis virus vectors expressing the Lassa virus glycoprotein. After a single intramuscular injection , test primates have survived lethal challenge, while showing no clinical symptoms. There is no vaccine for humans as of 2023. Researchers at the United States Army Medical Research Institute of Infectious Diseases facility had a promising vaccine candidate in 2002. They have developed a replication -competent vaccine against Lassa virus based on recombinant vesicular stomatitis virus vectors expressing the Lassa virus glycoprotein. After a single intramuscular injection , test primates have survived lethal challenge, while showing no clinical symptoms. Treatment is directed at addressing dehydration and improving symptoms. All persons suspected of Lassa fever infection should be admitted to isolation facilities and their body fluids and excreta properly disposed of. [ citation needed ] The antiviral medication ribavirin has been recommended, but evidence to support its use is weak. Some evidence has found that it may worsen outcomes in certain cases. Fluid replacement, blood transfusions, and medication for low blood pressure may be required. Intravenous interferon therapy has also been used. When Lassa fever infects pregnant women late in their third trimester, inducing delivery is necessary for the mother to have a good chance of survival. This is because the virus has an affinity for the placenta and other highly vascular tissues. The fetus has only a one in ten chance of survival no matter what course of action is taken; hence, the focus is always on saving the life of the mother. Following delivery, women should receive the same treatment as other people with Lassa fever. [ citation needed ]The antiviral medication ribavirin has been recommended, but evidence to support its use is weak. Some evidence has found that it may worsen outcomes in certain cases. Fluid replacement, blood transfusions, and medication for low blood pressure may be required. Intravenous interferon therapy has also been used. When Lassa fever infects pregnant women late in their third trimester, inducing delivery is necessary for the mother to have a good chance of survival. This is because the virus has an affinity for the placenta and other highly vascular tissues. The fetus has only a one in ten chance of survival no matter what course of action is taken; hence, the focus is always on saving the life of the mother. Following delivery, women should receive the same treatment as other people with Lassa fever. [ citation needed ]About 15–20% of hospitalized people with Lassa fever will die from the illness. The overall case fatality rate is estimated to be 1%, but during epidemics , mortality can climb as high as 50%. The mortality rate is greater than 80% when it occurs in pregnant women during their third trimester; fetal death also occurs in nearly all those cases. Abortion decreases the risk of death to the mother. Some survivors experience lasting effects of the disease, and can include partial or complete deafness. Because of treatment with ribavirin , fatality rates have declined. There are about 300,000 to 500,000 cases which result in 5,000 deaths a year. One estimate places the number as high as 3 million cases per year. Estimates of Lassa fever are complicated by the lack of easy-available diagnosis, limited public health surveillance infrastructure, and high clustering of incidence near high intensity sampling. The infection affects females 1.2 times more than males. The age group predominantly infected is 21–30 years. Lassa high risk areas are near the western and eastern extremes of West Africa. As of 2018, the Lassa belt includes Guinea, Nigeria, Sierra Leone and Liberia. As of 2003, 10-16% of people in Sierra Leone and Liberia admitted to hospital had the virus. The case fatality rate for those who are hospitalized for the disease is about 15-20%. Research showed a twofold increase risk of infection for those living in close proximity to someone with infection symptoms within the last year. [ citation needed ] The high risk areas cannot be well defined by any known biogeographical or environmental breaks except for the multimammate rat, particularly Guinea ( Kindia , Faranah and Nzérékoré regions), Liberia (mostly in Lofa , Bong , and Nimba counties), Nigeria (in about 10 of 36 states) and Sierra Leone (typically from Kenema and Kailahun districts). It is less common in the Central African Republic, Mali, Senegal and other nearby countries, and less common yet in Ghana and the Democratic Republic of the Congo. Benin had its first confirmed cases in 2014, and Togo had its first confirmed cases in 2016. As of 2013, the spread of Lassa outside of West Africa had been very limited. Twenty to thirty cases had been described in Europe, as being caused by importation through infected individuals. These cases found outside of West Africa were found to have a high fatality risk because of the delay of diagnosis and treatment due to being unaware of the risk associated with the symptoms. Imported cases have not manifested in larger epidemics outside of Africa due to a lack of human to human transmission in hospital settings. An exception had occurred in 2003 when a healthcare worker became infected before the person showed clear symptoms. An outbreak of Lassa fever occurred in Nigeria during 2018 and spread to 18 of the country's states; it was the largest outbreak of Lassa recorded. On 25 February 2018, there were 1081 suspected cases and 90 reported deaths; 317 of the cases and 72 deaths were confirmed as Lassa which increased to a total of 431 reported cases in 2018. The total cases in Nigeria in 2019 was 810 with 167 deaths, the largest case fatality rate (23.3%) until then. The epidemic started from the second week of the January. By the tenth week the total number of cases has risen to 855 and deaths to 144, the case fatality rate of 16.8%. On the 8th of December 2021, the Nigeria Centre for Disease Control (NCDC) was notified of the death of two persons from Lassa fever. The epidemic took a new form, from 3 to 30 January 2022, 211 laboratory confirmed Lassa fever cases including 40 deaths (case fatality ratio: 19%) have been cumulatively reported in 14 of the 36 Nigerian states and the Federal Capital Territory across the country. In total from January until March, 132 deaths have been reported with a case fatality rate (CFR) of 19.1% which is lower than the CFR for the same period in 2021 (21.0%). Lassa high risk areas are near the western and eastern extremes of West Africa. As of 2018, the Lassa belt includes Guinea, Nigeria, Sierra Leone and Liberia. As of 2003, 10-16% of people in Sierra Leone and Liberia admitted to hospital had the virus. The case fatality rate for those who are hospitalized for the disease is about 15-20%. Research showed a twofold increase risk of infection for those living in close proximity to someone with infection symptoms within the last year. [ citation needed ] The high risk areas cannot be well defined by any known biogeographical or environmental breaks except for the multimammate rat, particularly Guinea ( Kindia , Faranah and Nzérékoré regions), Liberia (mostly in Lofa , Bong , and Nimba counties), Nigeria (in about 10 of 36 states) and Sierra Leone (typically from Kenema and Kailahun districts). It is less common in the Central African Republic, Mali, Senegal and other nearby countries, and less common yet in Ghana and the Democratic Republic of the Congo. Benin had its first confirmed cases in 2014, and Togo had its first confirmed cases in 2016. As of 2013, the spread of Lassa outside of West Africa had been very limited. Twenty to thirty cases had been described in Europe, as being caused by importation through infected individuals. These cases found outside of West Africa were found to have a high fatality risk because of the delay of diagnosis and treatment due to being unaware of the risk associated with the symptoms. Imported cases have not manifested in larger epidemics outside of Africa due to a lack of human to human transmission in hospital settings. An exception had occurred in 2003 when a healthcare worker became infected before the person showed clear symptoms. An outbreak of Lassa fever occurred in Nigeria during 2018 and spread to 18 of the country's states; it was the largest outbreak of Lassa recorded. On 25 February 2018, there were 1081 suspected cases and 90 reported deaths; 317 of the cases and 72 deaths were confirmed as Lassa which increased to a total of 431 reported cases in 2018. The total cases in Nigeria in 2019 was 810 with 167 deaths, the largest case fatality rate (23.3%) until then. The epidemic started from the second week of the January. By the tenth week the total number of cases has risen to 855 and deaths to 144, the case fatality rate of 16.8%. On the 8th of December 2021, the Nigeria Centre for Disease Control (NCDC) was notified of the death of two persons from Lassa fever. The epidemic took a new form, from 3 to 30 January 2022, 211 laboratory confirmed Lassa fever cases including 40 deaths (case fatality ratio: 19%) have been cumulatively reported in 14 of the 36 Nigerian states and the Federal Capital Territory across the country. In total from January until March, 132 deaths have been reported with a case fatality rate (CFR) of 19.1% which is lower than the CFR for the same period in 2021 (21.0%). An outbreak of Lassa fever occurred in Nigeria during 2018 and spread to 18 of the country's states; it was the largest outbreak of Lassa recorded. On 25 February 2018, there were 1081 suspected cases and 90 reported deaths; 317 of the cases and 72 deaths were confirmed as Lassa which increased to a total of 431 reported cases in 2018. The total cases in Nigeria in 2019 was 810 with 167 deaths, the largest case fatality rate (23.3%) until then. The epidemic started from the second week of the January. By the tenth week the total number of cases has risen to 855 and deaths to 144, the case fatality rate of 16.8%. On the 8th of December 2021, the Nigeria Centre for Disease Control (NCDC) was notified of the death of two persons from Lassa fever. The epidemic took a new form, from 3 to 30 January 2022, 211 laboratory confirmed Lassa fever cases including 40 deaths (case fatality ratio: 19%) have been cumulatively reported in 14 of the 36 Nigerian states and the Federal Capital Territory across the country. In total from January until March, 132 deaths have been reported with a case fatality rate (CFR) of 19.1% which is lower than the CFR for the same period in 2021 (21.0%). Lassa fever is endemic in Liberia. From 1 January 2017 through 23 January 2018, 91 suspected cases were reported from six counties: Bong, Grand Bassa, Grand Kru, Lofa, Margibi, and Nimba. Thirty-three of these cases were laboratory confirmed, including 15 deaths (case fatality rate for confirmed cases = 45.4%). In February 2020, a total of 24 confirmed cases with nine associated deaths has been reported from nine health districts in six counties. Grand Bossa and Bong counties account for 20 of the confirmed cases. The disease was identified in Nigeria in 1969. It is named after the town of Lassa, where it was discovered. A prominent expert in the disease, Aniru Conteh , died from the disease. The Lassa virus is one of several viruses identified by WHO as a likely cause of a future epidemic. They therefore list it for urgent research and development to develop new diagnostic tests, vaccines, and medicines. In 2007, SIGA Technologies , studied a medication in guinea pig with Lassa fever. Work on a vaccine is continuing, with multiple approaches showing positive results in animal trials.

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Crimean-Congo haemorrhagic fever

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Hantavirus hemorrhagic fever with renal syndrome

Hantavirus hemorrhagic fever with renal syndrome ( HFRS ) is a group of clinically similar illnesses caused by species of hantaviruses . It is also known as Korean hemorrhagic fever and epidemic hemorrhagic fever . It is found in Europe, Asia, and Africa. The species that cause HFRS include Hantaan orthohantavirus , Dobrava-Belgrade orthohantavirus , Saaremaa virus , Seoul orthohantavirus , Puumala orthohantavirus and other orthohantaviruses. Of these species, Hantaan River virus and Dobrava-Belgrade virus cause the most severe form of the syndrome and have the highest morbidity rates. When caused by the Puumala virus, it is also called nephropathia epidemica . This infection is known as sorkfeber (vole fever) in Swedish, myyräkuume (vole fever) in Finnish, and musepest (mouse plague) in Norwegian. Both HFRS and hantavirus pulmonary syndrome (HPS) are caused by hantaviruses, specifically when humans inhale aerosolized excrements of infected rodents. Both diseases appear to be immunopathologic , and inflammatory mediators are important in causing the clinical manifestations. Symptoms of HFRS usually develop within one to two weeks after exposure to infectious material, but in rare cases, they may take up to eight weeks to develop. In Nephropathia epidemica, the incubation period is three weeks. Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash. Later symptoms can include low blood pressure, acute shock, vascular leakage, and acute kidney failure, which can cause severe fluid overload. The severity of the disease varies depending upon the virus causing the infection. Hantaan and Dobrava virus infections usually cause severe symptoms, while Seoul, Saaremaa, and Puumala virus infections are usually more moderate. Complete recovery can take weeks or months. The course of the illness can be split into five phases: This syndrome can also be fatal. In some cases, it has been known to cause permanent renal failure. Hantaviruses infect various rodents, generally without causing disease. Transmission by aerosolized rodent excreta still remains the only known way the virus is transmitted to humans. In general, droplet and/or fomite transfer has not been shown in the hantaviruses in either the pulmonary or hemorrhagic forms. For Nephropathia epidemica, the bank vole is the reservoir for the virus, which humans contract through inhalation of aerosolised vole droppings. HFRS is difficult to diagnose on clinical grounds alone and serological evidence is often needed. A fourfold rise in IgG antibody titer in a one-week interval and the presence of the IgM type of antibodies against hantaviruses are good evidence for an acute hantavirus infection. HFRS should be suspected in patients with acute febrile flu-like illness, kidney failure of unknown origin and sometimes liver dysfunction. Rodent control in and around the home remains the primary prevention strategy, as well as eliminating contact with rodents in the workplace and campsite. Closed storage sheds and cabins are often ideal sites for rodent infestations. Airing out of such spaces prior to use is recommended. Avoid direct contact with rodent droppings and wear a mask to avoid inhalation of aerosolized rodent secretions. There is no cure for HFRS. Treatment involves supportive therapy including renal dialysis. Treatment with ribavirin in China and Korea, administered within seven days of onset of fever, resulted in a reduced mortality as well as shortened course of illness. HFRS is primarily a Eurasian disease, whereas HPS appears to be confined to the Americas. The geography is directly related to the indigenous rodent hosts and the viruses that coevolved with them. Although fatal in a small percentage of cases, nephropathia epidemica is generally milder than the HFRS that is caused by hantaviruses in other parts of the world. HFRS was the subject of an episode of the television series M*A*S*H. In season 8, episode 9 the 4077th dealt with a condition, with similar symptoms to HFRS, called "Korean Hemorrhagic Fever".

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Crimean-Congo haemorrhagic fever

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Faizullah Kakar

Faizullah Kakar ( Pashto : فيض الله كاكر , Persian : فيض الله كاكر , born 24 December 1950) is a retired Afghan epidemiologist. He retired from civil service on 30 March 2020. He previously served as the Chief of Staff to President Ashraf Ghani , the Afghan Ambassador to Qatar, the Adviser to president for Health and Education, and the Deputy Minister of Public Health for the Islamic Republic of Afghanistan . Kakar also previously served as the Presidential National Focal Point for Polio Eradication for Afghanistan, as part of the Bill and Melinda Gates Foundation effort to eradicate polio. Kakar has written and spoken internationally about numerous challenges faced in Afghanistan, including infectious disease epidemics, maternal mortality and the dangers of herbicides used to eradicate poppy. Kakar attended secondary school at Lycee Habibia in Kabul, Afghanistan. In 1975, Kakar graduated with a bachelor's degree in biology from Earlham College , Richmond, Indiana. In 1977, Kakar received a master's degree in Toxicology from Indiana University , Indianapolis, Indiana. In 1982, Kakar completed his doctoral degree (PhD) in Epidemiology from the University of Washington , Seattle, Washington. From 1981 to 1988, Kakar also served on the board of the Islamic School of Seattle , Washington. At the University of Washington , from 1984 to 1986, Kakar worked as a Clinical Assistant Professor in the Department of Epidemiology. In 1986, he was hired as a Staff Scientist at Cancer Control Research Unit of the Fred Hutchinson Cancer Research Center in Seattle , Washington . In 1988, he moved to Peshawar, Pakistan where he founded the Research and Advisory Council of Afghanistan (RACA). He served first as General Chief of the Division of Preventive Medicine of the Ministry of Public Health , Interim Islamic Government of Afghanistan. In 1990, Kakar served as Dean for the College of Medicine, then Vice-Chancellor before serving as Chancellor of Islamic University of Afghanistan (IUA) in Peshawar , Pakistan until 1996. From 1993 to 1995, Kakar also served as the Deputy Minister of Public Health for the Islamic Government of Afghanistan in Kabul , Afghanistan . In 1997, Kakar moved to Islamabad , Pakistan where he was selected by United Nations as the Medical Officer/Epidemiologist for World Health Organization (WHO). Kakar was first to develop and coin the term "Disease Early Warning System" (DEWS) in Pakistan, which is a surveillance system recognized now throughout the world and being copied in many countries. Kakar worked for the WHO for 7 years. In 2005, Kakar was again tapped as Deputy Minister for the Ministry of Public Health by the Government of Islamic Republic of Afghanistan in Kabul where he served for 5 years. Kakar opposed mass spraying of fields with herbicide glyphosate to eradicate poppy, which was later proven to be carcinogenic in humans. In 2009, he was promoted to Minister Adviser to the President on Health and Education Affairs. In 2012, he was also assigned to be the Presidential Focal Point for Polio Eradication, a position with global support as Afghanistan remains one of only three countries in the world with endemic polio transmission. In 2016, Kakar was appointed as the Afghan Ambassador to Doha, Qatar where he worked closely to support efforts for peace in Afghanistan. Dr. Faizullah Kakar, Afghanistan's deputy minister of public health, was the member of Karzai's cabinet best qualified to evaluate the risks that might be posed to the Afghan people by aerial spraying. He had grown up in Kabul but earned a bachelor's degree in biology from Earlham College in Indiana, a master's degree in toxicology from Indiana University, and a doctoral degree in epidemiology from the University of Washington. He had later worked for the World Health Organization in Pakistan. Kakar understood that glyphosate was widely used by American gardeners and farmers, who poured about one hundred million pounds of the stuff on their lawns and fields every year. The Environmental Protection Agency judged that glyphosate had "low toxicity" for humans, "slight toxicity" for birds, and was harmless to fish and bees. Apart from requiring a warning label, the E.P.A. did not restrict the chemical giant Monsanto from manufacturing or selling Roundup to Americans. Yet Kakar seriously doubted that it made sense to douse Afghan fields with the stuff. "You are telling us about how safe it is," he told Doug Wankel, the D.E.A. official in the Kabul embassy. "Remember D.D.T.?" He was referring to dichloro-diphenyl-trichloroethane, a synthetic insecticide developed in the 1940s. Initially popular and believed to be safe, D.D.T. turned out to be highly persistent in the environment and was ultimately classified by the E.P.A. as a probable human carcinogen. Kakar pointed out that Afghanistan had "a much more agricultural economy" than the United States, that runoff from fields went straight to local water supplies, and that many Afghans were "totally dependent" on farming. The country could not afford a massive spraying campaign based on current scientific assessments, only to discover later that glyphosate was not as safe as advertised. Kakar propounded his views before Karzai and the full Afghan cabinet. He said that while the Americans "used thousands of pounds of the same spray safely in California," the United States did much better at protecting its water sources, whereas Afghans "drink from open watercourses." "This is the most popular chemical in the world," Bill Wood pointed out. Yet Wood and other advocates for spraying underestimated the asymmetries of power in these arguments with Afghans. Most Afghan decision makers (and for that matter, many Colombians) were not in a position to independently judge the longterm public health risks of glyphosate. And why should they accept E.P.A. judgments as gospel, given America's own history of regulatory failures involving chemicals and public health? Amrullah Saleh and other cabinet ministers objected to the spraying plan on the grounds that "Taliban propaganda would profit greatly from any spraying." Karzai's instinctive sense was that if farmers and itinerant poppy pickers in Helmand and Kandahar looked up and saw American helicopters thundering over the horizon as dusters poured chemicals onto their fields, they would recall the atrocities of Soviet aerial warfare and blame Hamid Karzai. Gradually during 2007, while remaining cautious about offending President Bush, but with the unified support of his cabinet, Karzai made his position clear to the Americans: He opposed aerial spraying. He also opposed any role for the U.S. military in fighting drug production. Faizullah Kakar. Practical Recommendations for Better Health (Farsi). 132 pp. April 2014. AAZEM Publications, Kabul. Anbrasi Edward, Binay Kumar, Faizullah Kakar, Ahmad Shah Salehi, Gilbert Burnham, David H. Peters. Configuring Balanced Scorecards for Measuring Health System Performance: Evidence from 5 Years' Evaluation in Afghanistan. PLoS Medicine 2011. Jul; 8 (7): e1001066. Epub 2011 Jul 26. Leslie T, Whitehouse CA, Yingst S, Baldwin C, Kakar F, Mofleh J, Hami AS, Mustafa L, Omar F, Ayazi E, Rossi C, Noormal B, Ziar N, Kakar R. Outbreak of gastroenteritis caused by Yersinia pestis in Afghanistan. Epidemiol Infect. 2011 May;139 (5):728-35. Faizullah Kakar, Zarif Akbarian, Toby Leslie, Mir Lais Mustafa, John Watson, Hans P. van Egmond, Mohammad Fahim Omar, and Jawad Mofleh. An Outbreak of Hepatic Veno-Occlusive Disease in Western Afghanistan Associated with Exposure to Wheat Flour Contaminated with Pyrrolizidine Alkaloids. Journal of Toxicology 2010. 28; 2010:313280. Epub 2010 Jun 28. Tharani Kandasamy, Richard J. Guidotti, Ana P. Betrán, Jennifer Harris-Requejo, Farima Hakimi, Paul F. Van Look, F. Kakar, Cesarean delivery surveillance system at a maternity hospital in Kabul, Afghanistan, International Journal of Gynecology and Obstetrics 104:14–17 (2009). Guidotti, Richard J., Kandasamy, Tharani, Betrán, Ana Pilar, Merialdi, Mario, Hakimi, Farima, Van Look, Paul and Kakar, Faizullah. Monitoring perinatal outcomes in hospitals in Kabul, Afghanistan: The first step of a quality assurance process. The Journal of Maternal-Fetal & Neonatal Medicine, 2009. Apr; 22 (4):285-92. Faizullah Kakar, Abdul Hamid Ahmadzai, Najibullah Habib, Asadullah Taqdeer, Frederick Hartmann. A successful response to an outbreak of cholera in Afghanistan. Tropical Doctor, 2008. Jan; 38 (1):17-20. David H Peters, Ayan Ahmed Noor, Lakhwinder P singh, Faizullah Kakar, Peter M Hansen, Gilbert Burnham. A balanced scorecard for health services in Afghanistan. Bull World Health Org, 2007. Feb; 85 (2): 146–51. Faizullah Kakar. 2005. Infectious diseases during the Afghan War IN Surviving Crisis: How systems and communities cope with instability, insecurity and infection. Workshop Proceedings 3–7 April 2002, The International Conference Center, Manila Philippines. Eds Pilar Ramos-Jimenez, Johannes Sommerfeld, Anthony Zwi. Manila: SDRC, CLA, De La Salle University. Athar Saeed Dil, Faizullah Kakar, Muhammad Najeeb Durrani, Jaleel Kamran, Zafar Toor. Disease Surveillance and Control, Jointly Published by Epidemic Investigation Cell of National Institute of Health, Ministry of Health, Govt of Pakistan, WHO, and Global Infectious Disease Surveillance and Alert System (GIDSAS) of Johns Hopkins University USA Vol-4: 1, Jan-Mar 2004. Ghazala Ashfaq, Faizullah Kakar, Maqbool Ahmed. Association of Tubal Ligation or Abdominal Surgery with other Gynecological Illness. Pakistan J Med Res. Oct – Dec 2005; 44(4): 152–5, 2005. Ghazala Ashfaq, Faizullah Kakar, Maqbool Ahmed. Female Sterilization and its effects on women health. Pakistan J Med. Res. Oct – Dec 2003; 42 (4), 2003. Altaf Hussain Bosan, Hamayun Asghar, Athar Saeed Dil, Faizullah Kakar, Irtaza Ahmad, Agha Sadarruddin. Nomad index case responsible for Crimean Congo Haemorrhagic Fever (CCHF) outbreak in Pishin. Pakistan J. Med. Res. Oct – Dec 2003; 42(4): 200–1, 2003. Altaf Hussain Bosan, Hamayun Asghar, Athar Saeed Dill, Faizullah Kakar, Zafar Toor, Arshad Altaf, Arif Sarwari, Amna Rehana Siddiqui. Crimean Congo hemorrhagic fever (CCHF) outbreak in Karachi. Pakistan J. Med. Res. Jan – Mar 2002; 41(1): 36–8. Agha Mahboob, Raza Malik, Qais Mahmood Sikandar, Zahid Ishaq, Faizullah Kakar. Private practitioner survey in Pakistan regarding their knowledge, attitude and practice of diseases reporting. Pakistan J. Med. Res. Jan – Mar 2000; 39(1): 26–9; 42(4): 200–1, 2003. Altaf Hussain Bosan, Amanullah, Athar Saeed Dil, Faizullah Kakar, Agha Sadaruddin. The efficacy of intralesional treatment of Cutaneous Lieshmaniasis with Glucantime. Pakistan J. Med. Res. Vol.41, No.2, 2002. Altaf Hussain Bosan, Athar Saeed Dil, Faizullah Kakar, Sohail Zaidi, Agha Sadaruddin, Fayaz Ahmad. Measles mortality among Afghan refugee children. Pakistan J. Med. Res. Vol. 41, No 3, 2002 Altaf Hussain Bosan, Hamayun Asghar, Athar Saeed Dil, Faizullah Kakar, Zafar Toor Arshad Altaf, Arif Sarwari, Aman Rehana Siddique. Crimean Congo Haemorrhagic Fever outbreak in Karachi. Pakistan J Med. Res. Vol.41 No.1. 36–38. 2002. Aga MA, Sikander QM, Kakar F, Ishaq Z. Severe gastroenteritis outbreak in Rawalpindi. Pakistan J Med Res 2000; 39: 127-9 Kakar, F, Bassani F, Romer, CJ, Gunn, SWA. The Consequence of Land Mines on Public Health. Prehospital and Disaster Medicine. 11(1):2 2-10-1996 Kakar F, Kakar SR. Indicators of Child Morbidity and Mortality in Three Afghan Provinces. UNICEF, 1996. (41pp) Kakar F, Refreshing Your Wudhu is Healthy, Prolonging it is Harmful (in English & Dari) 21 pages. Institute of Public Health of Afghanistan, May, 1995. Kakar F. Tea and Your Health (Dari). Peshawar: RACA. 1992. (32 pp) (available at ACKU Library) Kakar F, Kakar SR. A new method of vital statistics collection in Afghanistan. Final Report to WHO on Pilot Project 1990. ALSO summarized in: A new method of vital statistics collection in Afghanistan. Proc. of RACA, August 4–6, 1991. Kakar F, Hursting S, Henderson MM, Thornquist M. Dietary sugar and breast cancer mortality: Epidemiologic evidence. Clin Nutr 9(2): 68–71, 1990. Kakar F, Thornquist M, Henderson MM, Klein R, et al. The effect of dietary sugar and dietary antioxidants on mammary tumor growth, lethality in BALB/c mice. Clin Nutr 9(2):62-7, 1990. Prentic RL, Kakar F, Hursting S, et al. Aspects of the rationale for the Women's Health Trial. J Natl Cancer Inst 80(11):802-814, 1988. Kakar F, Weiss N, Strite S. Non-contraceptive estrogen use and the risk of gallstone disease in women, Am J Public Health 78(5): 564–566, 1988. Kakar F, Weiss N, Strite S. Thiazide use and risk of cholescystectomy in women Am J Epidemiol 124 (3): 428–433, 1986. Kakar F, Henderson MM. Potential toxic side effects of folic acid. J Natl Cancer Inst 74:1, 1985. Kakar F, Henderson MM. Diet and breast cancer. Clinical Nutrition 4(4): 119–30, 1985. Faizullah Kakar. Risk factors for the occurrence of gallstone disease in women: a case-control study. PhD Dissertation. University of Washington 169. 1982. Faizullah Kakar. A proposed mechanism of gentamicin renal toxicity. Thesis for MSc. Dept of Toxicology. Indiana University. 1977.

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Crimean-Congo haemorrhagic fever

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Orthohantavirus

Hantavirus Orthohantavirus is a genus of single-stranded, enveloped, negative-sense RNA viruses in the family Hantaviridae within the order Bunyavirales . Members of this genus may be called orthohantaviruses or simply hantaviruses . Orthohantaviruses typically cause chronic asymptomatic infection in rodents . Humans may become infected with hantaviruses through contact with rodent urine, saliva, or feces. Some strains cause potentially fatal diseases in humans, such as hantavirus hemorrhagic fever with renal syndrome (HFRS), or hantavirus pulmonary syndrome (HPS), also known as hantavirus cardiopulmonary syndrome (HCPS), while others have not been associated with known human disease (e.g. Prospect Hill virus ). HPS (HCPS) is a "rare respiratory illness associated with the inhalation of aerosolized rodent excreta (urine and feces) contaminated by hantavirus particles". Human infections of hantaviruses have almost entirely been linked to human contact with rodent excrement; however, in 2005 and 2019, human-to-human transmission of the Andes virus was reported in South America. Orthohantaviruses are named for the Greek word ortho - meaning "straight" or "true" and for the Hantan River in South Korea , where the first member species ( Hantaan virus ) was identified and isolated in 1976 by Ho Wang Lee . Hantavirus infections in humans are associated with two diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), caused by Old World and New World hantaviruses, respectively. A common feature of the two diseases is increased vascular permeability, which causes hypotension , thrombocytopenia , and leukocytosis . The pulmonary illness is the more fatal of the two, whereas the hemorrhagic fever is much more common. Treatment for both is primarily supportive as there is no specific treatment for hantavirus infections. While many hantaviruses cause either of the two diseases, some are not known to cause illness, such as the Prospect Hill orthohantavirus . Hemorrhagic fever with renal syndrome (HFRS) is caused chiefly by hantaviruses in Asia and Europe. Clinical presentation varies from subclinical to fatal, depending on the virus. After an incubation period of 2–4 weeks, the typical illness starts with non-specific symptoms such as high fever, chills, headache, backache, abdominal pains, nausea, and vomiting. After the initial period, bleeding under the skin begins, often paired with low blood pressure, followed by further internal bleeding throughout the body. Renal dysfunction leading to further health issues begins thereafter, which may cause death. A more mild form of HFRS that occurs in Europe is called "nephropathia epidemica" (NE). Trench nephritis during World War I is now thought to have been HFRS. [ citation needed ] Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is usually caused by hantaviruses in the Americas. Its incubation period ranges from 16 to 24 days. Illness initially shows similar symptoms as HFRS. After a few days of non-specific symptoms, sudden onset of progressive, or productive, coughing, shortness of breath, and elevated heart rate occur due to fluid buildup in the lungs . These symptoms are accompanied by impairment of lymphoid organs . Death from cardiovascular shock may occur rapidly after the appearance of severe symptoms. While HCPS is typically associated with New World hantaviruses, the Puumala orthohantavirus in Europe has also caused the syndrome on rare occasions. Hantaviruses are transmitted by contact with the bodily fluids of rodents, particularly from saliva from bites and especially from inhalation of viral particles from urine and feces in aerosols . The manner of transmission is the same for both diseases caused by hantaviruses. Among the HCPS-causing hantaviruses is the Andes orthohantavirus , which is the only hantavirus confirmed to be capable of spreading from person to person, though this is rare. Hemorrhagic fever with renal syndrome (HFRS) is caused chiefly by hantaviruses in Asia and Europe. Clinical presentation varies from subclinical to fatal, depending on the virus. After an incubation period of 2–4 weeks, the typical illness starts with non-specific symptoms such as high fever, chills, headache, backache, abdominal pains, nausea, and vomiting. After the initial period, bleeding under the skin begins, often paired with low blood pressure, followed by further internal bleeding throughout the body. Renal dysfunction leading to further health issues begins thereafter, which may cause death. A more mild form of HFRS that occurs in Europe is called "nephropathia epidemica" (NE). Trench nephritis during World War I is now thought to have been HFRS. [ citation needed ]Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is usually caused by hantaviruses in the Americas. Its incubation period ranges from 16 to 24 days. Illness initially shows similar symptoms as HFRS. After a few days of non-specific symptoms, sudden onset of progressive, or productive, coughing, shortness of breath, and elevated heart rate occur due to fluid buildup in the lungs . These symptoms are accompanied by impairment of lymphoid organs . Death from cardiovascular shock may occur rapidly after the appearance of severe symptoms. While HCPS is typically associated with New World hantaviruses, the Puumala orthohantavirus in Europe has also caused the syndrome on rare occasions. Hantaviruses are transmitted by contact with the bodily fluids of rodents, particularly from saliva from bites and especially from inhalation of viral particles from urine and feces in aerosols . The manner of transmission is the same for both diseases caused by hantaviruses. Among the HCPS-causing hantaviruses is the Andes orthohantavirus , which is the only hantavirus confirmed to be capable of spreading from person to person, though this is rare. Hantavirus virions are about 80–120 nm in diameter. The lipid bilayer of the viral envelope is about 5 nm thick and is embedded with viral surface proteins to which sugar residues are attached. These glycoproteins, known as Gn and Gc, are encoded by the M segment of the viral genome. They tend to associate ( heterodimerize ) with each other and have both an interior tail and an exterior domain that extends to about 6 nm beyond the envelope surface. [ citation needed ] Inside the envelope are the nucleocapsids. These are composed of many copies of the nucleocapsid protein N, which interact with the three segments of the viral genome to form helical structures. The virally encoded RNA polymerase is also found in the interior. By mass, the virion is greater than 50% protein, 20–30% lipid, and 2–7% carbohydrate. The density of the virions is 1.18 g/cm 3 . These features are common to all members of the family Hantaviridae . [ citation needed ] The genome of hantaviruses is negative-sense, single-stranded RNA . Their genomes are composed of three segments: the small (S), medium (M), and large (L) segments. The S segment, 1–3 kilobases (kb) in length, encodes for the nucleocapsid (N) protein. The M segment, 3.2–4.9 kb in length, encodes a glycoprotein precursor polyprotein that is co-translationally cleaved into the envelope glycoproteins Gn and Gc, alternatively called G1 and G2. The L segment, 6.8–12 kb in length, encodes the L protein which functions primarily as the viral RNA-dependent RNA polymerase used for transcription and replication. Within virions , the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5′ and 3′ terminal sequences of genomic segments. [ citation needed ] As with other Bunyavirales , each of the three segments has a consensus 3′-terminal nucleotide sequence (AUCAUCAUC), which is complementary to the 5′-terminal sequence and is distinct from those of the other four genera in the family. These sequences appear to form panhandle structure which seem likely to play a role in replication and encapsidation facilitated by binding with the viral nucleocapsid (N) protein. The large segment is 6530–6550 nucleotides (nt) in length, the medium is 3613–3707 nt in length and the small is 1696–2083 nt in length. [ citation needed ] No nonstructural proteins are known, unlike the other genera in this family. At the 5′ and 3′ of each segment are short noncoding sequences: the noncoding segment in all sequences at the 5′ end is 37–51 nt. The 3′ noncoding regions differ: L segment 38–43 nt; M segment 168–229 nt; and S segment 370–730 nt. The 3′ end of the S segment is conserved between the genera suggesting a functional role. [ citation needed ] Viral entry into host cells initiates by binding to surface cell receptors. Integrins are considered to be the main receptors for hantaviruses in vitro , but complement decay-accelerating factor (DAF) and globular heads of complement C1q receptor (gC1qR) have mediated attachment in cultured cells too. Entry may proceed through a number of possible routes, including clathrin -dependent endocytosis , clathrin-independent receptor-mediated endocytosis, and micro pinocytosis . Viral particles are then transported to late endosomes . Gc-mediated membrane fusion with the endosomal membrane , triggered by low pH , releases the nucleocapsid into the cytoplasm . After the release of the nucleocapsids into cytoplasm, the complexes are targeted to the endoplasmic reticulum–Golgi intermediate compartments (ERGIC) through microtubular -associated movement resulting in the formation of viral factories at ERGIC. [ citation needed ] These factories then facilitate transcription and subsequent translation of the viral proteins. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this cap snatching , the mRNAs of hantaviruses are capped and contain nontemplated 5′-terminal extensions. The G1 (or Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex , where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae . Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis . [ citation needed ] The pathogenesis of hantavirus infections is unclear as there is a lack of animal models to describe it (rats and mice do not seem to acquire severe disease). While the primary site of viral replication in the body is not known, in HFRS the main effect is in the blood vessels while in HPS most symptoms are associated with the lungs. In HFRS, there are increased vascular permeability and decreased blood pressure due to endothelial dysfunction and the most dramatic damage is seen in the kidneys, whereas in HPS, the lungs, spleen, and gall bladder are most affected. Early symptoms of HPS tend to present similarly to the flu (muscle aches, fever and fatigue) and usually appear around 2 to 3 weeks after exposure. Later stages of the disease (about 4 to 10 days after symptoms start) include difficulty breathing, shortness of breath and coughing. Findings of significant congruence between phylogenies of hantaviruses and phylogenies of their rodent reservoirs have led to the theory that rodents, although infected by the virus, are not harmed by it because of long-standing hantavirus–rodent host coevolution , although findings in 2008 led to new hypotheses regarding hantavirus evolution. Various hantaviruses have been found to infect multiple rodent species, and cases of cross-species transmission ( host switching ) have been recorded. Additionally, rates of substitution based on nucleotide sequence data reveal that hantavirus clades and rodent subfamilies may not have diverged at the same time. Furthermore, as of 2007 hantaviruses have been found in multiple species of non-rodent shrews and moles. Taking into account the inconsistencies in the theory of coevolution, it was proposed in 2009 that the patterns seen in hantaviruses in relation to their reservoirs could be attributed to preferential host switching directed by geographical proximity and adaptation to specific host types. Another proposal from 2010 is that geographical clustering of hantavirus sequences may have been caused by an isolation-by-distance mechanism. Upon comparison of the hantaviruses found in hosts of orders Rodentia and Eulipotyphla , it was proposed in 2011 that the hantavirus evolutionary history is a mix of both host switching and codivergence and that ancestral shrews or moles, rather than rodents, may have been the early original hosts of ancient hantaviruses. A Bayesian analysis in 2014 suggested a common origin for these viruses ~2000 years ago. The association with particular rodent families appears to have been more recent. The viruses carried by the subfamilies Arvicolinae and Murinae originated in Asia 500–700 years ago. These subsequently spread to Africa , Europe , North America and Siberia possibly carried by their hosts. The species infecting the subfamily Neotominae evolved 500–600 years ago in Central America and then spread toward North America. The species infecting Sigmodontinae evolved in Brazil 400 years ago. Their ancestors may have been a Neotominae-associated virus from northern South America. The evolution of shrew -borne hantaviruses appears to have involved natural occurrences of homologous recombination events and the reassortment of genome segments. The evolution of Tula orthohantavirus carried by the European common vole also appears to have involved homologous recombination events. Hantavirus virions are about 80–120 nm in diameter. The lipid bilayer of the viral envelope is about 5 nm thick and is embedded with viral surface proteins to which sugar residues are attached. These glycoproteins, known as Gn and Gc, are encoded by the M segment of the viral genome. They tend to associate ( heterodimerize ) with each other and have both an interior tail and an exterior domain that extends to about 6 nm beyond the envelope surface. [ citation needed ] Inside the envelope are the nucleocapsids. These are composed of many copies of the nucleocapsid protein N, which interact with the three segments of the viral genome to form helical structures. The virally encoded RNA polymerase is also found in the interior. By mass, the virion is greater than 50% protein, 20–30% lipid, and 2–7% carbohydrate. The density of the virions is 1.18 g/cm 3 . These features are common to all members of the family Hantaviridae . [ citation needed ]The genome of hantaviruses is negative-sense, single-stranded RNA . Their genomes are composed of three segments: the small (S), medium (M), and large (L) segments. The S segment, 1–3 kilobases (kb) in length, encodes for the nucleocapsid (N) protein. The M segment, 3.2–4.9 kb in length, encodes a glycoprotein precursor polyprotein that is co-translationally cleaved into the envelope glycoproteins Gn and Gc, alternatively called G1 and G2. The L segment, 6.8–12 kb in length, encodes the L protein which functions primarily as the viral RNA-dependent RNA polymerase used for transcription and replication. Within virions , the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5′ and 3′ terminal sequences of genomic segments. [ citation needed ] As with other Bunyavirales , each of the three segments has a consensus 3′-terminal nucleotide sequence (AUCAUCAUC), which is complementary to the 5′-terminal sequence and is distinct from those of the other four genera in the family. These sequences appear to form panhandle structure which seem likely to play a role in replication and encapsidation facilitated by binding with the viral nucleocapsid (N) protein. The large segment is 6530–6550 nucleotides (nt) in length, the medium is 3613–3707 nt in length and the small is 1696–2083 nt in length. [ citation needed ] No nonstructural proteins are known, unlike the other genera in this family. At the 5′ and 3′ of each segment are short noncoding sequences: the noncoding segment in all sequences at the 5′ end is 37–51 nt. The 3′ noncoding regions differ: L segment 38–43 nt; M segment 168–229 nt; and S segment 370–730 nt. The 3′ end of the S segment is conserved between the genera suggesting a functional role. [ citation needed ]Viral entry into host cells initiates by binding to surface cell receptors. Integrins are considered to be the main receptors for hantaviruses in vitro , but complement decay-accelerating factor (DAF) and globular heads of complement C1q receptor (gC1qR) have mediated attachment in cultured cells too. Entry may proceed through a number of possible routes, including clathrin -dependent endocytosis , clathrin-independent receptor-mediated endocytosis, and micro pinocytosis . Viral particles are then transported to late endosomes . Gc-mediated membrane fusion with the endosomal membrane , triggered by low pH , releases the nucleocapsid into the cytoplasm . After the release of the nucleocapsids into cytoplasm, the complexes are targeted to the endoplasmic reticulum–Golgi intermediate compartments (ERGIC) through microtubular -associated movement resulting in the formation of viral factories at ERGIC. [ citation needed ] These factories then facilitate transcription and subsequent translation of the viral proteins. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this cap snatching , the mRNAs of hantaviruses are capped and contain nontemplated 5′-terminal extensions. The G1 (or Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex , where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae . Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis . [ citation needed ]The pathogenesis of hantavirus infections is unclear as there is a lack of animal models to describe it (rats and mice do not seem to acquire severe disease). While the primary site of viral replication in the body is not known, in HFRS the main effect is in the blood vessels while in HPS most symptoms are associated with the lungs. In HFRS, there are increased vascular permeability and decreased blood pressure due to endothelial dysfunction and the most dramatic damage is seen in the kidneys, whereas in HPS, the lungs, spleen, and gall bladder are most affected. Early symptoms of HPS tend to present similarly to the flu (muscle aches, fever and fatigue) and usually appear around 2 to 3 weeks after exposure. Later stages of the disease (about 4 to 10 days after symptoms start) include difficulty breathing, shortness of breath and coughing. Findings of significant congruence between phylogenies of hantaviruses and phylogenies of their rodent reservoirs have led to the theory that rodents, although infected by the virus, are not harmed by it because of long-standing hantavirus–rodent host coevolution , although findings in 2008 led to new hypotheses regarding hantavirus evolution. Various hantaviruses have been found to infect multiple rodent species, and cases of cross-species transmission ( host switching ) have been recorded. Additionally, rates of substitution based on nucleotide sequence data reveal that hantavirus clades and rodent subfamilies may not have diverged at the same time. Furthermore, as of 2007 hantaviruses have been found in multiple species of non-rodent shrews and moles. Taking into account the inconsistencies in the theory of coevolution, it was proposed in 2009 that the patterns seen in hantaviruses in relation to their reservoirs could be attributed to preferential host switching directed by geographical proximity and adaptation to specific host types. Another proposal from 2010 is that geographical clustering of hantavirus sequences may have been caused by an isolation-by-distance mechanism. Upon comparison of the hantaviruses found in hosts of orders Rodentia and Eulipotyphla , it was proposed in 2011 that the hantavirus evolutionary history is a mix of both host switching and codivergence and that ancestral shrews or moles, rather than rodents, may have been the early original hosts of ancient hantaviruses. A Bayesian analysis in 2014 suggested a common origin for these viruses ~2000 years ago. The association with particular rodent families appears to have been more recent. The viruses carried by the subfamilies Arvicolinae and Murinae originated in Asia 500–700 years ago. These subsequently spread to Africa , Europe , North America and Siberia possibly carried by their hosts. The species infecting the subfamily Neotominae evolved 500–600 years ago in Central America and then spread toward North America. The species infecting Sigmodontinae evolved in Brazil 400 years ago. Their ancestors may have been a Neotominae-associated virus from northern South America. The evolution of shrew -borne hantaviruses appears to have involved natural occurrences of homologous recombination events and the reassortment of genome segments. The evolution of Tula orthohantavirus carried by the European common vole also appears to have involved homologous recombination events. Orthohantaviruses belong to the family Hantaviridae and members of both the genus and the family are called hantaviruses. The genus also belongs to the subfamily Mammantavirinae , the mammalian hantaviruses, with three other genera. Orthohantaviruses specifically are mammalian hantaviruses that are transmitted among rodents. The genus contains these 38 species: Hantaviruses that were formerly classified as species in this genus and which were not reassigned as member viruses of any existing species include: Isla Vista hantavirus , also called Isla Vista virus Muleshoe hantavirus , also called Muleshoe virus Rio Segundo hantavirus , also called Rio Segundo virusAccording to the U.S. CDC, the best prevention against contracting hantavirus is to eliminate or minimize contact with rodents in the home, workplace, or campsite. As the virus can be transmitted by rodent saliva, excretions, and bites, control of rats and mice in areas frequented by humans is key for disease prevention. General prevention can be accomplished by disposing of rodent nests, sealing any cracks and holes in homes where mice or rats could enter, setting traps, or laying down poisons or using natural predators such as cats in the home. The duration that hantaviruses remain infectious in the environment varies based on factors such as the rodent's diet, temperature, humidity, and whether indoors or outdoors. The viruses have been demonstrated to remain active for 2–3 days at normal room temperature, while ultraviolet rays in direct sunlight kill them within a few hours. Rodent droppings or urine of indeterminate age, though, should always be treated as infectious. As of 2021 [ update ] , no vaccines against hantaviruses have been approved by the U.S. FDA, but whole virus inactivated bivalent vaccines against Hantaan virus and Seoul virus are available in China and South Korea. In both countries, the use of the vaccine, combined with other preventive measures, has significantly reduced the incidence of hantavirus infections. Apart from these vaccines, four types of vaccines have been researched: DNA vaccines targeting the M genome segment and the S genome segment, subunit vaccines that use recombinant Gn, Gc, and N proteins of the virus, virus vector vaccines that have recombinant hantavirus proteins inserted in them, and virus-like particle vaccines that contain viral proteins, but lack genetic material. Of these, only DNA vaccines have entered into clinical trials. As of 2021 [ update ] , no vaccines against hantaviruses have been approved by the U.S. FDA, but whole virus inactivated bivalent vaccines against Hantaan virus and Seoul virus are available in China and South Korea. In both countries, the use of the vaccine, combined with other preventive measures, has significantly reduced the incidence of hantavirus infections. Apart from these vaccines, four types of vaccines have been researched: DNA vaccines targeting the M genome segment and the S genome segment, subunit vaccines that use recombinant Gn, Gc, and N proteins of the virus, virus vector vaccines that have recombinant hantavirus proteins inserted in them, and virus-like particle vaccines that contain viral proteins, but lack genetic material. Of these, only DNA vaccines have entered into clinical trials. Ribavirin may be a drug for HPS and HFRS, but its effectiveness remains unknown; still, spontaneous recovery is possible with supportive treatment. People with suspected hantavirus infection may be admitted to a hospital, and given oxygen and mechanical ventilation support to help them breathe during the acute pulmonary stage with severe respiratory distress. Immunotherapy, administration of human neutralizing antibodies during acute phases of hantavirus, has been studied only in mice, hamsters, and rats. No controlled clinical trials have been reported. Hantavirus infections have been reported from all continents except Australia. Regions especially affected by HFRS include China , the Korean Peninsula , Russia (Hantaan, Puumala, and Seoul viruses), and Northern and Western Europe ( Puumala and Dobrava virus). Regions with the highest incidences of hantavirus pulmonary syndrome include Argentina , Chile , Brazil , the United States , Canada , and Panama . [ citation needed ] In 2010, a novel hantavirus, Sangassou virus , was isolated in Africa, which causes HFRS. In China, Hong Kong, the Korean Peninsula, and Russia, HFRS is caused by Hantaan, Puumala, and Seoul viruses. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. As of 2005 [ update ] , no human infections have been reported in Australia, though rodents were found to carry antibodies. In Europe, two hantaviruses – Puumala and Dobrava-Belgrade viruses – are known to cause HFRS. Puumala usually causes a generally mild disease, nephropathia epidemica , which typically presents with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision. Dobrava infections are similar, except that they often also have hemorrhagic complications. [ citation needed ] Puumala virus is carried by its rodent host, the bank vole ( Clethrionomys glareolus ), and is present throughout most of Europe, except for the Mediterranean region. Four Dobrava virus genotypes are known, each carried by a different rodent species. Genotype Dobrava is found in the yellow-necked mouse ( Apodemus flavicollis ), genotypes Saaremaa and Kurkino in the striped field mouse ( Apodemus agrarius ), and genotype Sochi in the Black Sea field mouse ( Apodemus ponticus ). [ citation needed ] In 2017 alone, the Robert Koch Institute (RKI) in Germany received 1,713 notifications of hantavirus infections. The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . Agents of HPS found in South America include the Andes virus (also called Oran, Castelo de Sonhos – Portuguese for "Castle of Dreams", Lechiguanas, Juquitiba, Araraquara, and Bermejo virus, among many other synonyms), which is the only hantavirus that has shown an interpersonal form of transmission, and the Laguna Negra virus , an extremely close relative of the previously known Rio Mamore virus. [ citation needed ] Rodents that have been shown to carry hantaviruses include Abrothrix longipilis and Oligoryzomys longicaudatus . In 2010, a novel hantavirus, Sangassou virus , was isolated in Africa, which causes HFRS. In China, Hong Kong, the Korean Peninsula, and Russia, HFRS is caused by Hantaan, Puumala, and Seoul viruses. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. As of 2005 [ update ] , no human infections have been reported in Australia, though rodents were found to carry antibodies. In Europe, two hantaviruses – Puumala and Dobrava-Belgrade viruses – are known to cause HFRS. Puumala usually causes a generally mild disease, nephropathia epidemica , which typically presents with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision. Dobrava infections are similar, except that they often also have hemorrhagic complications. [ citation needed ] Puumala virus is carried by its rodent host, the bank vole ( Clethrionomys glareolus ), and is present throughout most of Europe, except for the Mediterranean region. Four Dobrava virus genotypes are known, each carried by a different rodent species. Genotype Dobrava is found in the yellow-necked mouse ( Apodemus flavicollis ), genotypes Saaremaa and Kurkino in the striped field mouse ( Apodemus agrarius ), and genotype Sochi in the Black Sea field mouse ( Apodemus ponticus ). [ citation needed ] In 2017 alone, the Robert Koch Institute (RKI) in Germany received 1,713 notifications of hantavirus infections. The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . Agents of HPS found in South America include the Andes virus (also called Oran, Castelo de Sonhos – Portuguese for "Castle of Dreams", Lechiguanas, Juquitiba, Araraquara, and Bermejo virus, among many other synonyms), which is the only hantavirus that has shown an interpersonal form of transmission, and the Laguna Negra virus , an extremely close relative of the previously known Rio Mamore virus. [ citation needed ] Rodents that have been shown to carry hantaviruses include Abrothrix longipilis and Oligoryzomys longicaudatus . Hantavirus HFRS was likely first referenced in China in the 12th century. The first clinical recognition was in 1931 in northeast China. Around the same time in the 1930s, NE was identified in Sweden. HFRS came to the recognition of western physicians during the Korean War between 1951 and 1954 when more than 3,000 United Nations soldiers fell ill in an outbreak. In 1976, the first pathogenic hantavirus, the Hantaan orthohantavirus , was isolated from rodents near the Hantan River in South Korea . Other prominent hantaviruses that cause HFRS, including the Dobrava-Belgrade orthohantavirus , Puumala orthohantavirus , and Seoul orthohantavirus , were identified in the years after then and are collectively referred to as the Old World hantaviruses. In 1993, an outbreak of HCPS , then unrecognized, occurred in the Four Corners region of the United States and led to the discovery of the Sin Nombre orthohantavirus . Since then, approximately 43 hantavirus strains, of which 20 are pathogenic, have been found in the Americas and are referred to as the New World hantaviruses. This includes the Andes orthohantavirus , one of the primary causes of HCPS in South America and the only hantavirus known to be capable of person-to-person transmission. In late medieval England a mysterious sweating sickness swept through the country in 1485 just before the Battle of Bosworth Field . Noting that the symptoms overlap with hantavirus pulmonary syndrome, several scientists have theorized that the virus may have been the cause of the disease. The hypothesis was criticized because sweating sickness was recorded as being transmitted from human to human, whereas hantaviruses were not known to spread in this way.

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Crimean-Congo haemorrhagic fever

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Thogotovirus

Thogoto-like viruses Thogotovirus is a genus of enveloped RNA viruses , one of seven genera in the virus family Orthomyxoviridae . Their single-stranded , negative-sense RNA genome has six or seven segments. Thogotoviruses are distinguished from most other orthomyxoviruses by being arboviruses – viruses that are transmitted by arthropods , in this case usually ticks . Thogotoviruses can replicate in both tick cells and vertebrate cells; one subtype has also been isolated from mosquitoes . A consequence of being transmitted by blood-sucking vectors is that the virus must spread systemically in the vertebrate host – unlike influenza viruses , which are transmitted by respiratory droplets and are usually confined to the respiratory system . The genus contains the species Thogoto thogotovirus and Dhori virus (DHOV), and the latter's subtype Batken virus, as well as the species or strains Araguari virus , Aransas Bay virus (ABV), Bourbon virus , Jos virus (JOSV) and Upolu virus (UPOV), which have yet to be confirmed by the International Committee on Taxonomy of Viruses (ICTV). A wide range of mammals are infected by members of the genus; some types also infect birds . THOV causes disease in livestock. THOV, DHOV and Bourbon virus can infect humans, and have occasionally been associated with human disease.THOV and DHOV were identified in the early 1960s in Kenya and India , respectively. Two cases of human disease associated with THOV occurred in 1966, and a Russian laboratory accident in the 1980s showed that DHOV can also cause disease in humans. The two viruses were originally considered to be bunyaviruses , but characterisation in the 1980s and early 1990s revealed similarities with influenza viruses . A genus of "Thogoto-like viruses" within Orthomyxoviridae was proposed in 1995, and recognised by the ICTV under the name Thogotovirus the following year. The name comes from Thogoto Forest in Kenya, where THOV was first discovered. Since then, sequence analysis of five viruses discovered in the 1960–70s but unclassified or tentatively assigned to Bunyaviridae led to their being proposed as additional members of the genus. A further proposed member of the genus was characterised by next-generation sequencing in 2014. The virus particle is enveloped . It is generally spherical or ovoid , with a diameter in the range 80–120 nm. Some filamentous forms are observed in THOV, Batken and Bourbon viruses . The single-stranded , – RNA genome is linear and segmented, with six or seven segments of 0.9–2.3 kb and a total size of around 10 kb. Reassortment of segments between strains has been observed in both ticks and mammals experimentally infected with more than one thogotovirus, but its significance in natural infections is unknown. The genome encodes 7–9 proteins, including the trimeric RNA polymerase enzyme (PA, PB1, PB2) and the structural proteins nucleoprotein (NP), which binds the viral genome; matrix protein (M1), which lines the envelope; and an envelope glycoprotein (GP), which acts as the virus receptor. The thogotovirus glycoprotein is not similar to the influenza virus glycoproteins ( haemagglutinin and neuraminidase ), and instead shows some similarities with the gp64 glycoprotein of baculoviruses , which infect insects. It also has some similarity with the haemagglutinin of Quaranfil virus of the related genus of tick-transmitted orthomyxoviruses Quaranjavirus . The mechanism by which thogotoviruses gained a baculovirus-like glycoprotein is unknown. Pat Nuttall and colleagues have speculated that the acquisition enabled these viruses to infect ticks. This apparent receptor specificity for arthropod cells does not prevent most thogotoviruses from infecting vertebrates. The thogotovirus glycoprotein is classified as a class III or γ penetrene, lacking the fusion peptide present in influenza haemagglutinin (a class I or α penetrene). THOV and JOSV also encode the protein M-long (ML), which counters the host's innate immunity , in particular by suppressing the production of interferon . This immune evasion is important for the virus to infect systemically in vertebrates , but is unnecessary in arthropods , which lack the interferon response. The mechanism of action of ML is completely different from the equivalent protein in influenza viruses ( NS1 ). As in all orthomyxoviruses, the largest three segments (1–3) encode the three subunits of the RNA polymerase. In thogotoviruses, segment 4 encodes the glycoprotein and segment 5 the nucleoprotein. The messenger RNA (mRNA) from segment 6 can be spliced to encode the matrix protein or unspliced to encode ML, which has 38 additional amino acids at its C-terminus . No product has yet been identified for the seventh segment, observed in DHOV. The receptor on the vertebrate host cell is sialic acid , which is bound by the viral glycoprotein. Entry is by endocytosis , with fusion of the viral and cell membranes occurring once the vesicle is acidified. In common with other orthomyxoviruses, viral transcription and replication both occur in the cell nucleus . In some members of the genus, replication has been shown to be sensitive to the Mx1/MxA protein, which is induced in mice and humans in response to interferon. In one study, this inhibitory effect was shown to be caused by MxA preventing the transport of the THOV genome into the nucleus. As orthomyxoviruses do not encode a capping enzyme, initiation of transcription involves the virus cutting the cap off the 5′-end of host mRNAs, so that the mRNA is recognised by the host translation machinery. A similar " cap snatching " process is used by other orthomyxoviruses, but a much longer host RNA sequence is cleaved along with the cap and incorporated into the viral mRNA. The virus assembles by the cell membrane and leaves the cell by budding. For THOV grown in baby hamster kidney cells , virus particles start to be released 6–8 hours after infection, with substantial quantities still being produced 24 hours after infection. This growth rate is slower than that of influenza viruses, and is more similar to Quaranfil virus. The genome encodes 7–9 proteins, including the trimeric RNA polymerase enzyme (PA, PB1, PB2) and the structural proteins nucleoprotein (NP), which binds the viral genome; matrix protein (M1), which lines the envelope; and an envelope glycoprotein (GP), which acts as the virus receptor. The thogotovirus glycoprotein is not similar to the influenza virus glycoproteins ( haemagglutinin and neuraminidase ), and instead shows some similarities with the gp64 glycoprotein of baculoviruses , which infect insects. It also has some similarity with the haemagglutinin of Quaranfil virus of the related genus of tick-transmitted orthomyxoviruses Quaranjavirus . The mechanism by which thogotoviruses gained a baculovirus-like glycoprotein is unknown. Pat Nuttall and colleagues have speculated that the acquisition enabled these viruses to infect ticks. This apparent receptor specificity for arthropod cells does not prevent most thogotoviruses from infecting vertebrates. The thogotovirus glycoprotein is classified as a class III or γ penetrene, lacking the fusion peptide present in influenza haemagglutinin (a class I or α penetrene). THOV and JOSV also encode the protein M-long (ML), which counters the host's innate immunity , in particular by suppressing the production of interferon . This immune evasion is important for the virus to infect systemically in vertebrates , but is unnecessary in arthropods , which lack the interferon response. The mechanism of action of ML is completely different from the equivalent protein in influenza viruses ( NS1 ). As in all orthomyxoviruses, the largest three segments (1–3) encode the three subunits of the RNA polymerase. In thogotoviruses, segment 4 encodes the glycoprotein and segment 5 the nucleoprotein. The messenger RNA (mRNA) from segment 6 can be spliced to encode the matrix protein or unspliced to encode ML, which has 38 additional amino acids at its C-terminus . No product has yet been identified for the seventh segment, observed in DHOV. The receptor on the vertebrate host cell is sialic acid , which is bound by the viral glycoprotein. Entry is by endocytosis , with fusion of the viral and cell membranes occurring once the vesicle is acidified. In common with other orthomyxoviruses, viral transcription and replication both occur in the cell nucleus . In some members of the genus, replication has been shown to be sensitive to the Mx1/MxA protein, which is induced in mice and humans in response to interferon. In one study, this inhibitory effect was shown to be caused by MxA preventing the transport of the THOV genome into the nucleus. As orthomyxoviruses do not encode a capping enzyme, initiation of transcription involves the virus cutting the cap off the 5′-end of host mRNAs, so that the mRNA is recognised by the host translation machinery. A similar " cap snatching " process is used by other orthomyxoviruses, but a much longer host RNA sequence is cleaved along with the cap and incorporated into the viral mRNA. The virus assembles by the cell membrane and leaves the cell by budding. For THOV grown in baby hamster kidney cells , virus particles start to be released 6–8 hours after infection, with substantial quantities still being produced 24 hours after infection. This growth rate is slower than that of influenza viruses, and is more similar to Quaranfil virus. Most thogotoviruses have been shown to infect arthropods, generally hard or soft ticks , which are arachnids , but in one case mosquitoes , which are insects . Members also infect birds and a wide range of wild and domestic mammals , including marsupials , rodents , hares , mongoose , horses , camels , goats , sheep and cattle . Three types – THOV , DHOV and Bourbon virus – have been shown to infect humans. They have a wide geographical range. Transmission to vertebrates usually occurs via a tick vector . THOV persists in the tick, remaining in the organism as it goes through its developmental stages; this is called transstadial transmission . The virus can be transmitted to another host within a day of attachment to the host. THOV can be transmitted between ticks when they feed simultaneously on apparently uninfected guinea pigs , in the absence of a detectable level of virus in the blood. Such nonviraemic transmission has also been observed with other predominantly tick-transmitted RNA viruses, including bluetongue , Crimean–Congo haemorrhagic fever , louping ill , tick-borne encephalitis , vesicular stomatitis virus and West Nile virus viruses. Transmission of DHOV by respiratory aerosol has also been observed. No major pathological changes are observed in Rhipicephalus appendiculatus ticks infected with THOV. The virus is concentrated in the synganglion (the tick brain ) early on in the blood-feeding process, with the proportion of virus located in the salivary glands increasing during the late phase of blood-feeding. Lower levels of virus are found in the trachea , digestive tract and female sex organs, but not in the male sex organs or the excretory system . The high level of virus present in the synganglion has been proposed to help the virus persist through the metamorphosis of the tick, as the nervous system undergoes less remodeling than other systems. In the laboratory setting, several members of the genus cause severe disease in mice and hamsters . Systemic spread of the virus occurs, with pathological effects present in multiple organs and systems, including the brain , liver , lymphatic system , and sometimes the lungs and small intestine . Lymphocytes are a major target cell for DHOV. DHOV infection in mice resembles experimental influenza infection in mice and ferrets as well as fatal H5N1 influenza infection of humans, and has been proposed as a model for this disease. Natural infections with thogotoviruses in mammals generally do not appear to result in symptoms. THOV is a significant veterinary pathogen, for example, causing a febrile illness and abortion in sheep. As of February 2015, only eight cases of human disease associated with thogotoviruses have been reported: two with THOV, five with DHOV and one with Bourbon virus; there have been two fatalities. The incubation period for THOV is 4–5 days. All three viruses were associated with fever . THOV and DHOV also caused neurological symptoms : meningitis and neuromyelitis optica in the case of THOV; encephalitis in the case of DHOV. Hepatitis has been observed with THOV. The single case of disease in a person infected with Bourbon virus was associated with decreases in blood platelets and white cells ; no neurological symptoms were observed. Influenza-like respiratory symptoms have not been reported. No major pathological changes are observed in Rhipicephalus appendiculatus ticks infected with THOV. The virus is concentrated in the synganglion (the tick brain ) early on in the blood-feeding process, with the proportion of virus located in the salivary glands increasing during the late phase of blood-feeding. Lower levels of virus are found in the trachea , digestive tract and female sex organs, but not in the male sex organs or the excretory system . The high level of virus present in the synganglion has been proposed to help the virus persist through the metamorphosis of the tick, as the nervous system undergoes less remodeling than other systems. In the laboratory setting, several members of the genus cause severe disease in mice and hamsters . Systemic spread of the virus occurs, with pathological effects present in multiple organs and systems, including the brain , liver , lymphatic system , and sometimes the lungs and small intestine . Lymphocytes are a major target cell for DHOV. DHOV infection in mice resembles experimental influenza infection in mice and ferrets as well as fatal H5N1 influenza infection of humans, and has been proposed as a model for this disease. Natural infections with thogotoviruses in mammals generally do not appear to result in symptoms. THOV is a significant veterinary pathogen, for example, causing a febrile illness and abortion in sheep. As of February 2015, only eight cases of human disease associated with thogotoviruses have been reported: two with THOV, five with DHOV and one with Bourbon virus; there have been two fatalities. The incubation period for THOV is 4–5 days. All three viruses were associated with fever . THOV and DHOV also caused neurological symptoms : meningitis and neuromyelitis optica in the case of THOV; encephalitis in the case of DHOV. Hepatitis has been observed with THOV. The single case of disease in a person infected with Bourbon virus was associated with decreases in blood platelets and white cells ; no neurological symptoms were observed. Influenza-like respiratory symptoms have not been reported. No specific treatment or vaccine is available for thogotoviruses, as of February 2015. The antiviral drug ribavirin , which has a broad spectrum of activity that includes some other orthomyxoviruses, has been shown to inhibit DHOV replication in vitro in a single study. Supportive therapy is used for THOV disease, and has been recommended by the US Centers for Disease Control and Prevention for infection with Bourbon virus. As with other arboviruses , avoidance of contact with the vector is central to prevention. Two species have been confirmed by the ICTV , THOV and DHOV. The two viruses have a low degree of sequence identity (37% for the nucleoprotein; 31% for the envelope glycoprotein), and their antibodies do not crossreact. Batken virus is a subtype of DHOV. As of February 2015, a further five species or strains have been suggested as belonging to the genus. THOV was first isolated from ticks gathered from cattle in the Thogoto Forest region of Kenya , near Nairobi , in 1960, it is now known to be distributed across the African continent, and has also been found in Italy and Portugal in Europe, and Iran in the Middle East. Despite this wide geographical range, the virus shows only limited variation. Its vectors include various hard-bodied ticks, including Amblyomma , Hyalomma and Rhipicephalus species. Antibodies have been found to THOV in rats and many domestic animals, including goats, sheep, donkeys, camels, cattle and buffaloes, and the virus has been isolated from the wild banded mongoose ( Mongos mungo ). It causes significant livestock disease, including a febrile illness and abortion in sheep. In artificial laboratory infections, it is highly pathogenic in hamsters and also infects mice . The virus is known to infect humans in natural settings. The virus particle is generally spherical with some filamentous forms; the diameter is around 100 nm. The genome has six RNA segments. The Araguari virus was first isolated from a Gray four-eyed opossum ( Philander opossum ) in Serra do Navio , Amapá , Brazil in 1969. Its method of transmission is unknown. In laboratory infections, it is pathogenic to mice. The virion is around 105 nm in diameter. The genome has six RNA segments. Based on partial sequence data the virus was found to be most closely related to THOV. ABV was found in the soft-bodied tick genus Ornithodoros in seabird nests in southern Texas , USA, in 1975; it was the first member of the genus to be found in North America. No natural vertebrate host has been identified, but the virus is highly pathogenic to mice in laboratory infections. The virus particle is spherical or ovoid, with a range of sizes, from 75 nm × 85 nm to 120 nm × 140 nm. The genome has six RNA segments. It is most similar to UPOV, with some similarity to THOV and JOSV. JOSV was first isolated from the zebu ( Bos indicus ) in Jos , Nigeria in 1967. It has since been found infecting Amblyomma and Rhipicephalus hard-bodied ticks in several countries across Africa. In the laboratory it causes severe pathology in mice. The virus particle has a variable, usually ovoid, morphology with a diameter of 85–120 nm. The genome contains at least six RNA segments. It has some sequence similarities with UPOV and ABV. UPOV was first isolated on Upolu Cay in the Great Barrier Reef , Australia in 1966, from soft-bodied ticks of the species Ornithodoros capensis associated with the sooty tern ( Onychoprion fuscatus ). No natural vertebrate host has been identified, but the virus is highly pathogenic to mice in laboratory infections. The virion can either be spherical, with a diameter in the range 75–95 nm, or slightly ovoid, with a range of dimensions from 75 nm × 85 nm to 105 nm × 120 nm. The genome has six RNA segments. It is most similar to ABV, with some similarity to THOV and JOSV. DHOV was first isolated from Hyalomma dromedarii hard-bodied ticks infesting camels in Gujarat , India , in 1961. It has since been observed in eastern Russia , Pakistan , Egypt , Saudi Arabia , Kenya and southern Portugal . The vector is usually a species of Hyalomma , such as H. marginatum . Where DHOV is prevalent, antibodies to the virus have been documented in camels, goats, horses, cattle and humans. The virus has been isolated from a wild hare , Lepus europaeus . DHOV can infect humans by the aerosol route after accidental laboratory exposure, causing a febrile illness and encephalitis . Under laboratory conditions it is highly pathogenic for mice, and has been proposed as a model system for highly pathogenic influenza. It has also been shown to infect birds, with the virus being isolated from a cormorant , and antibodies being observed in waterfowl . DHOV has seven RNA segments. Batken virus was first isolated from hard-bodied ticks of the species Hyalomma plumbeum plumbeum infesting sheep near the town of Batken , Kirghizia , now in Kyrgyzstan , in 1970. It has also been found to infect mosquitoes of the species Aedes caspius Pallas and Culex hortensis Ficalbi , also in Kyrgyzstan. Its geographical range is limited to Central Asia, Transcaucasia and the area to the north of the Caspian Sea . In the laboratory it is highly pathogenic for mice, hamsters and chickens. The virion is variable in shape, with spherical and filamentous forms being observed; it has a diameter of 50–100 nm. Batken is considered a DHOV subtype; the viruses have a high degree of sequence identity (90% in the envelope glycoprotein; 96–98% in other proteins), and their antibodies crossreact. Bourbon virus was identified in 2014 by next-generation sequencing of a blood sample from a man from Bourbon County, Kansas , USA, who became ill a few days after being bitten by multiple ticks, and subsequently died. It is the only known thogotovirus to be associated with human disease in the Western hemisphere . As of February 2015, Bourbon virus has not been isolated from ticks, insects or non-human vertebrates. The virus is variable in shape, with filamentous as well as spherical forms; it has a diameter broadly in the range 100–130 nm. The genome contains at least six RNA segments. It is most similar to DHOV and Batken virus. Oz virus was first characterised in 2018 after isolation from the hard tick Amblyomma testudinarium in Ehime, Japan. [DOI: 10.1016/j.virusres.2018.03.004]. The first human case, a 70 year old female patient who died of myocarditis with isolation of Oz virus on autopsy, was reported on 23.6.2023 by the Japanese Ministry of Heath.THOV was first isolated from ticks gathered from cattle in the Thogoto Forest region of Kenya , near Nairobi , in 1960, it is now known to be distributed across the African continent, and has also been found in Italy and Portugal in Europe, and Iran in the Middle East. Despite this wide geographical range, the virus shows only limited variation. Its vectors include various hard-bodied ticks, including Amblyomma , Hyalomma and Rhipicephalus species. Antibodies have been found to THOV in rats and many domestic animals, including goats, sheep, donkeys, camels, cattle and buffaloes, and the virus has been isolated from the wild banded mongoose ( Mongos mungo ). It causes significant livestock disease, including a febrile illness and abortion in sheep. In artificial laboratory infections, it is highly pathogenic in hamsters and also infects mice . The virus is known to infect humans in natural settings. The virus particle is generally spherical with some filamentous forms; the diameter is around 100 nm. The genome has six RNA segments. The Araguari virus was first isolated from a Gray four-eyed opossum ( Philander opossum ) in Serra do Navio , Amapá , Brazil in 1969. Its method of transmission is unknown. In laboratory infections, it is pathogenic to mice. The virion is around 105 nm in diameter. The genome has six RNA segments. Based on partial sequence data the virus was found to be most closely related to THOV. ABV was found in the soft-bodied tick genus Ornithodoros in seabird nests in southern Texas , USA, in 1975; it was the first member of the genus to be found in North America. No natural vertebrate host has been identified, but the virus is highly pathogenic to mice in laboratory infections. The virus particle is spherical or ovoid, with a range of sizes, from 75 nm × 85 nm to 120 nm × 140 nm. The genome has six RNA segments. It is most similar to UPOV, with some similarity to THOV and JOSV. JOSV was first isolated from the zebu ( Bos indicus ) in Jos , Nigeria in 1967. It has since been found infecting Amblyomma and Rhipicephalus hard-bodied ticks in several countries across Africa. In the laboratory it causes severe pathology in mice. The virus particle has a variable, usually ovoid, morphology with a diameter of 85–120 nm. The genome contains at least six RNA segments. It has some sequence similarities with UPOV and ABV. UPOV was first isolated on Upolu Cay in the Great Barrier Reef , Australia in 1966, from soft-bodied ticks of the species Ornithodoros capensis associated with the sooty tern ( Onychoprion fuscatus ). No natural vertebrate host has been identified, but the virus is highly pathogenic to mice in laboratory infections. The virion can either be spherical, with a diameter in the range 75–95 nm, or slightly ovoid, with a range of dimensions from 75 nm × 85 nm to 105 nm × 120 nm. The genome has six RNA segments. It is most similar to ABV, with some similarity to THOV and JOSV. THOV was first isolated from ticks gathered from cattle in the Thogoto Forest region of Kenya , near Nairobi , in 1960, it is now known to be distributed across the African continent, and has also been found in Italy and Portugal in Europe, and Iran in the Middle East. Despite this wide geographical range, the virus shows only limited variation. Its vectors include various hard-bodied ticks, including Amblyomma , Hyalomma and Rhipicephalus species. Antibodies have been found to THOV in rats and many domestic animals, including goats, sheep, donkeys, camels, cattle and buffaloes, and the virus has been isolated from the wild banded mongoose ( Mongos mungo ). It causes significant livestock disease, including a febrile illness and abortion in sheep. In artificial laboratory infections, it is highly pathogenic in hamsters and also infects mice . The virus is known to infect humans in natural settings. The virus particle is generally spherical with some filamentous forms; the diameter is around 100 nm. The genome has six RNA segments. The Araguari virus was first isolated from a Gray four-eyed opossum ( Philander opossum ) in Serra do Navio , Amapá , Brazil in 1969. Its method of transmission is unknown. In laboratory infections, it is pathogenic to mice. The virion is around 105 nm in diameter. The genome has six RNA segments. Based on partial sequence data the virus was found to be most closely related to THOV. ABV was found in the soft-bodied tick genus Ornithodoros in seabird nests in southern Texas , USA, in 1975; it was the first member of the genus to be found in North America. No natural vertebrate host has been identified, but the virus is highly pathogenic to mice in laboratory infections. The virus particle is spherical or ovoid, with a range of sizes, from 75 nm × 85 nm to 120 nm × 140 nm. The genome has six RNA segments. It is most similar to UPOV, with some similarity to THOV and JOSV. JOSV was first isolated from the zebu ( Bos indicus ) in Jos , Nigeria in 1967. It has since been found infecting Amblyomma and Rhipicephalus hard-bodied ticks in several countries across Africa. In the laboratory it causes severe pathology in mice. The virus particle has a variable, usually ovoid, morphology with a diameter of 85–120 nm. The genome contains at least six RNA segments. It has some sequence similarities with UPOV and ABV. UPOV was first isolated on Upolu Cay in the Great Barrier Reef , Australia in 1966, from soft-bodied ticks of the species Ornithodoros capensis associated with the sooty tern ( Onychoprion fuscatus ). No natural vertebrate host has been identified, but the virus is highly pathogenic to mice in laboratory infections. The virion can either be spherical, with a diameter in the range 75–95 nm, or slightly ovoid, with a range of dimensions from 75 nm × 85 nm to 105 nm × 120 nm. The genome has six RNA segments. It is most similar to ABV, with some similarity to THOV and JOSV. DHOV was first isolated from Hyalomma dromedarii hard-bodied ticks infesting camels in Gujarat , India , in 1961. It has since been observed in eastern Russia , Pakistan , Egypt , Saudi Arabia , Kenya and southern Portugal . The vector is usually a species of Hyalomma , such as H. marginatum . Where DHOV is prevalent, antibodies to the virus have been documented in camels, goats, horses, cattle and humans. The virus has been isolated from a wild hare , Lepus europaeus . DHOV can infect humans by the aerosol route after accidental laboratory exposure, causing a febrile illness and encephalitis . Under laboratory conditions it is highly pathogenic for mice, and has been proposed as a model system for highly pathogenic influenza. It has also been shown to infect birds, with the virus being isolated from a cormorant , and antibodies being observed in waterfowl . DHOV has seven RNA segments. Batken virus was first isolated from hard-bodied ticks of the species Hyalomma plumbeum plumbeum infesting sheep near the town of Batken , Kirghizia , now in Kyrgyzstan , in 1970. It has also been found to infect mosquitoes of the species Aedes caspius Pallas and Culex hortensis Ficalbi , also in Kyrgyzstan. Its geographical range is limited to Central Asia, Transcaucasia and the area to the north of the Caspian Sea . In the laboratory it is highly pathogenic for mice, hamsters and chickens. The virion is variable in shape, with spherical and filamentous forms being observed; it has a diameter of 50–100 nm. Batken is considered a DHOV subtype; the viruses have a high degree of sequence identity (90% in the envelope glycoprotein; 96–98% in other proteins), and their antibodies crossreact. Bourbon virus was identified in 2014 by next-generation sequencing of a blood sample from a man from Bourbon County, Kansas , USA, who became ill a few days after being bitten by multiple ticks, and subsequently died. It is the only known thogotovirus to be associated with human disease in the Western hemisphere . As of February 2015, Bourbon virus has not been isolated from ticks, insects or non-human vertebrates. The virus is variable in shape, with filamentous as well as spherical forms; it has a diameter broadly in the range 100–130 nm. The genome contains at least six RNA segments. It is most similar to DHOV and Batken virus. Oz virus was first characterised in 2018 after isolation from the hard tick Amblyomma testudinarium in Ehime, Japan. [DOI: 10.1016/j.virusres.2018.03.004]. The first human case, a 70 year old female patient who died of myocarditis with isolation of Oz virus on autopsy, was reported on 23.6.2023 by the Japanese Ministry of Heath.DHOV was first isolated from Hyalomma dromedarii hard-bodied ticks infesting camels in Gujarat , India , in 1961. It has since been observed in eastern Russia , Pakistan , Egypt , Saudi Arabia , Kenya and southern Portugal . The vector is usually a species of Hyalomma , such as H. marginatum . Where DHOV is prevalent, antibodies to the virus have been documented in camels, goats, horses, cattle and humans. The virus has been isolated from a wild hare , Lepus europaeus . DHOV can infect humans by the aerosol route after accidental laboratory exposure, causing a febrile illness and encephalitis . Under laboratory conditions it is highly pathogenic for mice, and has been proposed as a model system for highly pathogenic influenza. It has also been shown to infect birds, with the virus being isolated from a cormorant , and antibodies being observed in waterfowl . DHOV has seven RNA segments. Batken virus was first isolated from hard-bodied ticks of the species Hyalomma plumbeum plumbeum infesting sheep near the town of Batken , Kirghizia , now in Kyrgyzstan , in 1970. It has also been found to infect mosquitoes of the species Aedes caspius Pallas and Culex hortensis Ficalbi , also in Kyrgyzstan. Its geographical range is limited to Central Asia, Transcaucasia and the area to the north of the Caspian Sea . In the laboratory it is highly pathogenic for mice, hamsters and chickens. The virion is variable in shape, with spherical and filamentous forms being observed; it has a diameter of 50–100 nm. Batken is considered a DHOV subtype; the viruses have a high degree of sequence identity (90% in the envelope glycoprotein; 96–98% in other proteins), and their antibodies crossreact. Bourbon virus was identified in 2014 by next-generation sequencing of a blood sample from a man from Bourbon County, Kansas , USA, who became ill a few days after being bitten by multiple ticks, and subsequently died. It is the only known thogotovirus to be associated with human disease in the Western hemisphere . As of February 2015, Bourbon virus has not been isolated from ticks, insects or non-human vertebrates. The virus is variable in shape, with filamentous as well as spherical forms; it has a diameter broadly in the range 100–130 nm. The genome contains at least six RNA segments. It is most similar to DHOV and Batken virus. Oz virus was first characterised in 2018 after isolation from the hard tick Amblyomma testudinarium in Ehime, Japan. [DOI: 10.1016/j.virusres.2018.03.004]. The first human case, a 70 year old female patient who died of myocarditis with isolation of Oz virus on autopsy, was reported on 23.6.2023 by the Japanese Ministry of Heath.

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Crimean-Congo haemorrhagic fever

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Kivu Ebola epidemic

The Kivu Ebola epidemic [note 2] was an outbreak of Ebola virus disease (EVD) mainly in eastern Democratic Republic of the Congo (DRC), and in other parts of Central Africa , from 2018 to 2020. Between 1 August 2018 and 25 June 2020 it resulted in 3,470 reported cases. The Kivu outbreak also affected Ituri Province , whose first case was confirmed on 13 August 2018. In November 2018, the outbreak became the biggest Ebola outbreak in the DRC's history, and had become the second-largest Ebola outbreak in recorded history worldwide, behind only the 2013–2016 Western Africa epidemic . In June 2019, the virus reached Uganda , having infected a 5-year-old Congolese boy who entered Uganda with his family, but was contained. A military conflict in the region that had begun in January 2015 hindered treatment and prevention efforts. The World Health Organization (WHO) described the combination of military conflict and civilian distress as a potential "perfect storm" that could lead to a rapid worsening of the outbreak. In May 2019, the WHO reported that since January, 85 health workers had been wounded or killed in 42 attacks on health facilities. In some areas, aid organizations had to stop their work due to violence. Health workers also had to deal with misinformation spread by opposing politicians. Due to the deteriorating security situation in North Kivu and surrounding areas, the WHO raised the risk assessment at the national and regional level from "high" to "very high" in September 2018. In October, the United Nations Security Council stressed that all armed hostility in the DRC should come to a stop to better fight the ongoing EVD outbreak. A confirmed case in Goma triggered the decision by the WHO to convene an emergency committee for the fourth time, and on 17 July 2019, the WHO announced a Public Health Emergency of International Concern (PHEIC), the highest level of alarm the WHO can sound. On 15 September 2019, some slowdown of EVD cases was noted by the WHO in DRC. However, contact tracing continued to be less than 100%; at the time, it was at 89%. As of mid-October the transmission of the virus had significantly reduced; by then it was confined to the Mandima region near where the outbreak began, and was only affecting 27 health zones in the DRC (down from a peak of 207). New cases dwindled to zero by 17 February 2020, but after 52 days without a case, surveillance and response teams on the ground confirmed three new cases of Ebola in Beni health zone in mid-April. On 25 June 2020, the outbreak was declared ended. As a new and separate outbreak, the Congolese health ministry reported on 1 June 2020 that there were cases of Ebola in Équateur Province in north-western DRC, described as the eleventh Ebola outbreak since records began. This separate outbreak was declared over as of 18 November following no reported cases for 42 days, and caused 130 cases and 55 deaths. As indicated below and per numbers offered by the United Nations the final death toll was 2,280 with a total of 3,470 cases in DRC in almost a two-year period. This was made very difficult due to the ongoing military attacks in the region which created a perfect storm for the virus, despite there being a vaccine. rVSV-ZEBOV or Ebola Zaire vaccine live, is a vaccine that prevents Ebola caused by the Zaire ebolavirus . The graph of reported cases reflects cases that were not able to have a laboratory test sample before burial as probable cases . On 1 August 2018, the North Kivu health division notified Congo's health ministry of 26 cases of hemorrhagic fever , including 20 deaths. Four of the six samples that were sent for analysis to the National Institute of Biological Research in Kinshasa came back positive for Ebola and an outbreak was declared on that date. The index case is believed to have been the death and unsafe burial of a 65-year-old woman on 25 July in Mangina, quickly followed by the deaths of seven close family members. This outbreak started just days after the end of the outbreak in Équateur province . On 1 August, just after the Ebola epidemic had been declared, Doctors Without Borders/Médecins Sans Frontières (MSF) arrived in Mangina, the point of origin of the outbreak, to mount a response. On 2 August, Oxfam indicated it would be taking part in the response to this latest outbreak in the DRC. On 4 August, the WHO indicated that the current situation in the DRC, due to several factors, warranted a "high risk assessment" at the national and regional level for public health. By 3 August, the virus had developed in multiple locations; cases were reported in five health zones – Beni , Butembo , Oicha , Musienene and Mabalako – in North Kivu province as well as Mandima and Mambasa in Ituri Province . However, one month later there had been confirmed cases only in the Mabalako, Mandima, Beni and Oicha health zones. The five suspected cases in the Mambasa Health Zone proved not to be EVD; it was not possible to confirm the one probable case in the Musienene Health Zone and the two probable cases in the Butembo Health Zone. No new cases had been recorded in any of those health zones. WHO chief Tedros Adhanom Ghebreyesu indicated on 15 August that the outbreak then in the DRC might be worse than the West African outbreak of 2013–2016, with the IRC connecting this to the ongoing Kivu conflict . The Kivu outbreak was the biggest of the ten recorded outbreaks recorded in the DRC. The first confirmed case in Butembo was announced on 4 September, the same day that it was announced that one of the cases registered at Beni had actually come from the Kalunguta Health Zone. In November, it was reported that the EVD outbreak ran across two provinces and 14 health zones. By 23 December, the EVD outbreak had spread to more health zones, and at that time 18 such areas had been affected. On 7 August 2018, the DRC Ministry of Public Health indicated that the total count had climbed to almost 90 cases, and the Uganda Ministry of Health issued an alert for extra surveillance as the outbreak was just 100 kilometres (62 mi) away from its border. Two days later the total count was nearly 100 cases. On 16 August, the United Kingdom indicated it would help with EVD diagnosis and monitoring in the DRC. On 17 August 2018, the WHO reported that there were around 1,500 " contacts ", while noting that certain conflict zones in the DRC that could not be reached might have contained more contacts. Some 954 contacts were successfully followed up on 18 August; however, Mandima Health Zone indicated resistance, so contacts were not followed up there. On 4 September, Butembo , a city with almost one million people and an international airport, recorded its first fatality in the Ebola outbreak. The city of Butembo, in the DRC, has trade links to nearby Uganda. On 24 September, it was reported that all contact tracing and vaccinations would stop for the foreseeable future in Beni due to a deadly attack by rebel groups the day before. On 25 September, Peter Salama of the WHO indicated that insecurity was obstructing efforts to stop the virus and believed a combination of factors could establish conditions for an epidemic. On 18 October, the U.S. Centers for Disease Control and Prevention (CDC) raised its travelers' alert to the DRC from a level 1 to level 2 for all U.S. travelers. On 26 October, the WHO indicated that half of confirmed cases were not showing any fever symptoms, thus making diagnosis more difficult. According to a September 2018 Lancet survey, 25% of respondents in Beni and Butembo believed the Ebola outbreak to be a hoax. These beliefs correlated with decreased likelihood of seeking healthcare or accepting vaccination. On 6 November 2018, the CDC indicated that the current outbreak in the east region of the DRC was potentially non-containable. This would be the first time since 1976 that an outbreak was not able to be curbed. On 13 November, the WHO indicated that the viral outbreak would last at least six months. On 29 December 2018, the DRC Ministry of Public Health announced that there had been "0 new confirmed cases detected because of the paralysis of the activities of the response in Beni, Butembo, Komanda and Mabalako" and no vaccination had occurred for three consecutive days. On 22 January, the total case count approached 1,000 cases, (951 suspected) in the DRC Ministry of Public Health situation report. The graphs below demonstrate the EVD intensity in different locations in the DRC, as well as in the West African epidemic of 2014–15 as a comparison: On 16 March 2019, the director of the CDC indicated that the outbreak in the DRC could last another year, additionally suggesting that vaccine supplies could run out. According to the WHO, resistance to vaccination in the Kaniyi Health Zone was ongoing as of March 2019. There was still a belief by some in surrounding areas that the epidemic was a hoax. Until the outbreak in North Kivu in 2018, no outbreak had surpassed 320 total cases in the Democratic Republic of the Congo. By 24 February 2019, the epidemic had surpassed 1,000 total cases (1,048). On 10 May 2019, the U.S. Centers for Disease Control and Prevention indicated that the outbreak could eventually surpass the West African epidemic. The 12 May 2019 issue of WHO Weekly Bulletin on Outbreaks and Other Emergencies, indicates that " continued increase in the number of new EVD cases in the Democratic Republic of the Congo is worrying...no end in sight to the difficult security situation ". On 25 November 2019, it was reported that violence had broken out in Beni again, to such a degree that some aid agencies had evacuated. According to the same report, around 300 individuals might have been exposed to EVD via an infected individual. On 14 July 2019, the first case of EVD was confirmed in the capital of North Kivu, Goma , a city with an international airport and a highly mobile population of 2 million people located near the DRC's eastern border with Rwanda . This case was a man who had passed through three health checkpoints, with different names on traveller lists. The WHO stated that he died in a treatment centre, whereas according to Reuters he died en route to a treatment centre. This case triggered the decision by the WHO to again reconvene an emergency committee, where the situation was officially declared a Public Health Emergency of International Concern . On 30 July, a second case of EVD was confirmed in the city of Goma, apparently not linked to the first case. Across the border from Goma in the country of Rwanda, Ebola simulation drills were being conducted at health facilities. A third case of EVD was confirmed in Goma on 1 August. On 22 August 2019, Nyiragongo Health Zone, the affected area on the outskirts of Goma, reached 21 days without further cases being confirmed. On 16 August 2019, it was reported that the Ebola virus disease had spread to a third province – South Kivu – via two new cases who had travelled from Beni, North Kivu. By 22 August the number of cases in Mwenga had risen to four, including one person at a health facility visited by the first case. In August 2018 a UN agency indicated that active screening was deployed to ensure that those leaving the DRC into Uganda were not infected with Ebola. The government of Uganda opened two Ebola treatment centers at the border with the DRC, though there had not yet been any confirmed cases in the country of Uganda. By 13 June 2019, nine treatment units were in place near the affected border. According to the International Red Cross , a "most likely scenario" entailed an asymptomatic case entering the country of Uganda undetected among the numerous refugees then coming from the DRC. On 20 September, Uganda indicated it was ready for immediate vaccination, should the Ebola virus be detected in any individual. On 21 September, officials of the DRC indicated a confirmed case of EVD at Lake Albert , an entry point into Uganda, though no cases were then confirmed within Ugandan territory. On 2 November, it was reported that the Ugandan government would start vaccinating health workers along the border with the DRC as a proactive measure against the virus. Vaccinations started on 7 November, and by 13 June 2019, 4,699 health workers at 165 sites had been vaccinated. Proactive vaccination was also carried out in South Sudan , with 1,471 health workers vaccinated by 7 May 2019. On 2 January 2019, it was reported that refugee movement from the DRC to Uganda had increased after the presidential elections. On 12 February, it was reported that 13 individuals had been isolated due to their contact with a suspected Ebola case in Uganda; lab results came back negative several hours later. On 11 June 2019, the WHO reported that the virus had spread to Uganda. A 5-year-old Congolese boy entered Uganda on the previous Sunday with his family to seek medical care. On 12 June, the WHO reported that the 5-year-old patient had died, while 2 more cases of Ebola infection within the same family were also confirmed. On 14 June it was reported that there were 112 contacts since EVD was first detected in Uganda. Ring vaccination of Ugandan contacts was scheduled to start on 15 June. As of 18 June 2019, 275 contacts had been vaccinated per the Uganda Ministry of Health. On 14 July, an individual entered the country of Uganda from DRC while symptomatic for EVD; a search for contacts in Mpondwe followed. On 24 July, Uganda marked the needed 42 day period without any EVD cases to be declared Ebola-free. On 29 August, a 9-year-old Congolese girl became the fourth individual in Uganda to test positive for EVD when she crossed from the DRC into the district of Kasese . In regards to possible EVD cases in Tanzania, the WHO stated on 21 September 2019 that "to date, the clinical details and the results of the investigation, including laboratory tests performed for differential diagnosis of these patients, have not been shared with WHO. The insufficient information received by WHO does not allow for a formulation of a hypotheses regarding the possible cause of the illness". On 27 September, the CDC and U.S. State Department alerted potential travellers to the possibility of unreported EVD cases within Tanzania. The Tanzanian Health Minister Ummy Mwalimu stated on 3 October 2019 that there was no Ebola outbreak in Tanzania. The WHO were provided with a preparedness update on 18 October which outlined a range of actions, and included commentary that since the outbreak commenced, there had been "29 alerts of Ebola suspect cases reported, 17 samples tested and were negative for Ebola (including 2 in September 2019)". On 29 December, an American physician who was exposed to the Ebola virus (and who was non-symptomatic) was evacuated, and taken to the University of Nebraska Medical Center . On 12 January, the individual was released after 21 days without symptoms. The table which follows indicates confirmed , probable and suspected cases, as well as deaths ; the table also indicates the multiple countries where these cases took place, during this outbreak. # These figures may increase when new cases are discovered, and fall consequently, when tests show cases were not Ebola-related. †DRC Ministry of Public Health ‡ indicates suspected cases were not counted towards CFR x indicates 42 days have passed since the last case and outbreak is declared over At the time of the epidemic, there were about 70 armed military groups, among them the Alliance of Patriots for a Free and Sovereign Congo and the Mai-Mayi Nduma défense du Congo-Rénové , in North Kivu. The fighting displaced thousands of individuals and seriously affected the response to the outbreak. According to the WHO, health care workers were to be accompanied by military personnel for protection and ring vaccination may not be possible. On 11 August 2018, it was reported that seven individuals were killed in Mayi-Moya due to a militant group, about 24 miles from the city of Beni where there were several EVD cases. On 24 August 2018, it was reported that an Ebola-stricken physician had been in contact with 97 individuals in an inaccessible military area, who hence could not be diagnosed. In September, it was reported that 2 peacekeepers were attacked and wounded by rebel groups in Beni, and 14 individuals were killed in a military attack. In September 2018, the WHO's Deputy Director-General for Emergency Preparedness and Response described the combination of military conflict and civilian distress as a potential "perfect storm" that could lead to a rapid worsening of the outbreak. On 20 October 2018, an armed rebel group in the DRC killed 13 civilians and took 12 children as hostages in Beni, which was then experiencing one of the worst outbreaks. On 11 November, six people were killed in an attack by an armed rebel group in Beni; as a consequence vaccinations were suspended there. Yet another attack reported on 17 November, in Beni by an armed rebel group forced the cessation of EVD containment efforts and WHO staff to evacuate to another DRC city for the time being. Beni continued to be the site of attacks by militant groups as 18 civilians were killed on 6 December. On 22 December, it was reported that elections for the President of the DRC would go forward despite the EVD outbreak, including in the Ebola-stricken area of Beni. Four days later, on 26 December, the DRC government reversed itself to indicate those Ebola-stricken areas, such as Beni, would not vote for several months; as a consequence election protesters ransacked an Ebola assessment center in Beni. Post election tensions continued when it was reported that the DRC government had cut off internet connectivity for the population, as the vote results were yet to be released. On 29 December 2018, Oxfam said it would suspend its work due to the ongoing violence in the DRC; on the same day, the International Rescue Committee suspended their Ebola support efforts as well. On 18 January, the African Union indicated that presidential election results announcements should be suspended in the DRC. On 1 August 2018, the North Kivu health division notified Congo's health ministry of 26 cases of hemorrhagic fever , including 20 deaths. Four of the six samples that were sent for analysis to the National Institute of Biological Research in Kinshasa came back positive for Ebola and an outbreak was declared on that date. The index case is believed to have been the death and unsafe burial of a 65-year-old woman on 25 July in Mangina, quickly followed by the deaths of seven close family members. This outbreak started just days after the end of the outbreak in Équateur province . On 1 August, just after the Ebola epidemic had been declared, Doctors Without Borders/Médecins Sans Frontières (MSF) arrived in Mangina, the point of origin of the outbreak, to mount a response. On 2 August, Oxfam indicated it would be taking part in the response to this latest outbreak in the DRC. On 4 August, the WHO indicated that the current situation in the DRC, due to several factors, warranted a "high risk assessment" at the national and regional level for public health. By 3 August, the virus had developed in multiple locations; cases were reported in five health zones – Beni , Butembo , Oicha , Musienene and Mabalako – in North Kivu province as well as Mandima and Mambasa in Ituri Province . However, one month later there had been confirmed cases only in the Mabalako, Mandima, Beni and Oicha health zones. The five suspected cases in the Mambasa Health Zone proved not to be EVD; it was not possible to confirm the one probable case in the Musienene Health Zone and the two probable cases in the Butembo Health Zone. No new cases had been recorded in any of those health zones. WHO chief Tedros Adhanom Ghebreyesu indicated on 15 August that the outbreak then in the DRC might be worse than the West African outbreak of 2013–2016, with the IRC connecting this to the ongoing Kivu conflict . The Kivu outbreak was the biggest of the ten recorded outbreaks recorded in the DRC. The first confirmed case in Butembo was announced on 4 September, the same day that it was announced that one of the cases registered at Beni had actually come from the Kalunguta Health Zone. In November, it was reported that the EVD outbreak ran across two provinces and 14 health zones. By 23 December, the EVD outbreak had spread to more health zones, and at that time 18 such areas had been affected. On 7 August 2018, the DRC Ministry of Public Health indicated that the total count had climbed to almost 90 cases, and the Uganda Ministry of Health issued an alert for extra surveillance as the outbreak was just 100 kilometres (62 mi) away from its border. Two days later the total count was nearly 100 cases. On 16 August, the United Kingdom indicated it would help with EVD diagnosis and monitoring in the DRC. On 17 August 2018, the WHO reported that there were around 1,500 " contacts ", while noting that certain conflict zones in the DRC that could not be reached might have contained more contacts. Some 954 contacts were successfully followed up on 18 August; however, Mandima Health Zone indicated resistance, so contacts were not followed up there. On 4 September, Butembo , a city with almost one million people and an international airport, recorded its first fatality in the Ebola outbreak. The city of Butembo, in the DRC, has trade links to nearby Uganda. On 24 September, it was reported that all contact tracing and vaccinations would stop for the foreseeable future in Beni due to a deadly attack by rebel groups the day before. On 25 September, Peter Salama of the WHO indicated that insecurity was obstructing efforts to stop the virus and believed a combination of factors could establish conditions for an epidemic. On 18 October, the U.S. Centers for Disease Control and Prevention (CDC) raised its travelers' alert to the DRC from a level 1 to level 2 for all U.S. travelers. On 26 October, the WHO indicated that half of confirmed cases were not showing any fever symptoms, thus making diagnosis more difficult. According to a September 2018 Lancet survey, 25% of respondents in Beni and Butembo believed the Ebola outbreak to be a hoax. These beliefs correlated with decreased likelihood of seeking healthcare or accepting vaccination. On 6 November 2018, the CDC indicated that the current outbreak in the east region of the DRC was potentially non-containable. This would be the first time since 1976 that an outbreak was not able to be curbed. On 13 November, the WHO indicated that the viral outbreak would last at least six months. On 29 December 2018, the DRC Ministry of Public Health announced that there had been "0 new confirmed cases detected because of the paralysis of the activities of the response in Beni, Butembo, Komanda and Mabalako" and no vaccination had occurred for three consecutive days. On 22 January, the total case count approached 1,000 cases, (951 suspected) in the DRC Ministry of Public Health situation report. The graphs below demonstrate the EVD intensity in different locations in the DRC, as well as in the West African epidemic of 2014–15 as a comparison: On 16 March 2019, the director of the CDC indicated that the outbreak in the DRC could last another year, additionally suggesting that vaccine supplies could run out. According to the WHO, resistance to vaccination in the Kaniyi Health Zone was ongoing as of March 2019. There was still a belief by some in surrounding areas that the epidemic was a hoax. Until the outbreak in North Kivu in 2018, no outbreak had surpassed 320 total cases in the Democratic Republic of the Congo. By 24 February 2019, the epidemic had surpassed 1,000 total cases (1,048). On 10 May 2019, the U.S. Centers for Disease Control and Prevention indicated that the outbreak could eventually surpass the West African epidemic. The 12 May 2019 issue of WHO Weekly Bulletin on Outbreaks and Other Emergencies, indicates that " continued increase in the number of new EVD cases in the Democratic Republic of the Congo is worrying...no end in sight to the difficult security situation ". On 25 November 2019, it was reported that violence had broken out in Beni again, to such a degree that some aid agencies had evacuated. According to the same report, around 300 individuals might have been exposed to EVD via an infected individual. On 14 July 2019, the first case of EVD was confirmed in the capital of North Kivu, Goma , a city with an international airport and a highly mobile population of 2 million people located near the DRC's eastern border with Rwanda . This case was a man who had passed through three health checkpoints, with different names on traveller lists. The WHO stated that he died in a treatment centre, whereas according to Reuters he died en route to a treatment centre. This case triggered the decision by the WHO to again reconvene an emergency committee, where the situation was officially declared a Public Health Emergency of International Concern . On 30 July, a second case of EVD was confirmed in the city of Goma, apparently not linked to the first case. Across the border from Goma in the country of Rwanda, Ebola simulation drills were being conducted at health facilities. A third case of EVD was confirmed in Goma on 1 August. On 22 August 2019, Nyiragongo Health Zone, the affected area on the outskirts of Goma, reached 21 days without further cases being confirmed. On 16 August 2019, it was reported that the Ebola virus disease had spread to a third province – South Kivu – via two new cases who had travelled from Beni, North Kivu. By 22 August the number of cases in Mwenga had risen to four, including one person at a health facility visited by the first case. On 7 August 2018, the DRC Ministry of Public Health indicated that the total count had climbed to almost 90 cases, and the Uganda Ministry of Health issued an alert for extra surveillance as the outbreak was just 100 kilometres (62 mi) away from its border. Two days later the total count was nearly 100 cases. On 16 August, the United Kingdom indicated it would help with EVD diagnosis and monitoring in the DRC. On 17 August 2018, the WHO reported that there were around 1,500 " contacts ", while noting that certain conflict zones in the DRC that could not be reached might have contained more contacts. Some 954 contacts were successfully followed up on 18 August; however, Mandima Health Zone indicated resistance, so contacts were not followed up there. On 4 September, Butembo , a city with almost one million people and an international airport, recorded its first fatality in the Ebola outbreak. The city of Butembo, in the DRC, has trade links to nearby Uganda. On 24 September, it was reported that all contact tracing and vaccinations would stop for the foreseeable future in Beni due to a deadly attack by rebel groups the day before. On 25 September, Peter Salama of the WHO indicated that insecurity was obstructing efforts to stop the virus and believed a combination of factors could establish conditions for an epidemic. On 18 October, the U.S. Centers for Disease Control and Prevention (CDC) raised its travelers' alert to the DRC from a level 1 to level 2 for all U.S. travelers. On 26 October, the WHO indicated that half of confirmed cases were not showing any fever symptoms, thus making diagnosis more difficult. According to a September 2018 Lancet survey, 25% of respondents in Beni and Butembo believed the Ebola outbreak to be a hoax. These beliefs correlated with decreased likelihood of seeking healthcare or accepting vaccination. On 6 November 2018, the CDC indicated that the current outbreak in the east region of the DRC was potentially non-containable. This would be the first time since 1976 that an outbreak was not able to be curbed. On 13 November, the WHO indicated that the viral outbreak would last at least six months. On 29 December 2018, the DRC Ministry of Public Health announced that there had been "0 new confirmed cases detected because of the paralysis of the activities of the response in Beni, Butembo, Komanda and Mabalako" and no vaccination had occurred for three consecutive days. On 22 January, the total case count approached 1,000 cases, (951 suspected) in the DRC Ministry of Public Health situation report. The graphs below demonstrate the EVD intensity in different locations in the DRC, as well as in the West African epidemic of 2014–15 as a comparison: On 16 March 2019, the director of the CDC indicated that the outbreak in the DRC could last another year, additionally suggesting that vaccine supplies could run out. According to the WHO, resistance to vaccination in the Kaniyi Health Zone was ongoing as of March 2019. There was still a belief by some in surrounding areas that the epidemic was a hoax. Until the outbreak in North Kivu in 2018, no outbreak had surpassed 320 total cases in the Democratic Republic of the Congo. By 24 February 2019, the epidemic had surpassed 1,000 total cases (1,048). On 10 May 2019, the U.S. Centers for Disease Control and Prevention indicated that the outbreak could eventually surpass the West African epidemic. The 12 May 2019 issue of WHO Weekly Bulletin on Outbreaks and Other Emergencies, indicates that " continued increase in the number of new EVD cases in the Democratic Republic of the Congo is worrying...no end in sight to the difficult security situation ". On 25 November 2019, it was reported that violence had broken out in Beni again, to such a degree that some aid agencies had evacuated. According to the same report, around 300 individuals might have been exposed to EVD via an infected individual. On 14 July 2019, the first case of EVD was confirmed in the capital of North Kivu, Goma , a city with an international airport and a highly mobile population of 2 million people located near the DRC's eastern border with Rwanda . This case was a man who had passed through three health checkpoints, with different names on traveller lists. The WHO stated that he died in a treatment centre, whereas according to Reuters he died en route to a treatment centre. This case triggered the decision by the WHO to again reconvene an emergency committee, where the situation was officially declared a Public Health Emergency of International Concern . On 30 July, a second case of EVD was confirmed in the city of Goma, apparently not linked to the first case. Across the border from Goma in the country of Rwanda, Ebola simulation drills were being conducted at health facilities. A third case of EVD was confirmed in Goma on 1 August. On 22 August 2019, Nyiragongo Health Zone, the affected area on the outskirts of Goma, reached 21 days without further cases being confirmed. On 16 August 2019, it was reported that the Ebola virus disease had spread to a third province – South Kivu – via two new cases who had travelled from Beni, North Kivu. By 22 August the number of cases in Mwenga had risen to four, including one person at a health facility visited by the first case. In August 2018 a UN agency indicated that active screening was deployed to ensure that those leaving the DRC into Uganda were not infected with Ebola. The government of Uganda opened two Ebola treatment centers at the border with the DRC, though there had not yet been any confirmed cases in the country of Uganda. By 13 June 2019, nine treatment units were in place near the affected border. According to the International Red Cross , a "most likely scenario" entailed an asymptomatic case entering the country of Uganda undetected among the numerous refugees then coming from the DRC. On 20 September, Uganda indicated it was ready for immediate vaccination, should the Ebola virus be detected in any individual. On 21 September, officials of the DRC indicated a confirmed case of EVD at Lake Albert , an entry point into Uganda, though no cases were then confirmed within Ugandan territory. On 2 November, it was reported that the Ugandan government would start vaccinating health workers along the border with the DRC as a proactive measure against the virus. Vaccinations started on 7 November, and by 13 June 2019, 4,699 health workers at 165 sites had been vaccinated. Proactive vaccination was also carried out in South Sudan , with 1,471 health workers vaccinated by 7 May 2019. On 2 January 2019, it was reported that refugee movement from the DRC to Uganda had increased after the presidential elections. On 12 February, it was reported that 13 individuals had been isolated due to their contact with a suspected Ebola case in Uganda; lab results came back negative several hours later. On 11 June 2019, the WHO reported that the virus had spread to Uganda. A 5-year-old Congolese boy entered Uganda on the previous Sunday with his family to seek medical care. On 12 June, the WHO reported that the 5-year-old patient had died, while 2 more cases of Ebola infection within the same family were also confirmed. On 14 June it was reported that there were 112 contacts since EVD was first detected in Uganda. Ring vaccination of Ugandan contacts was scheduled to start on 15 June. As of 18 June 2019, 275 contacts had been vaccinated per the Uganda Ministry of Health. On 14 July, an individual entered the country of Uganda from DRC while symptomatic for EVD; a search for contacts in Mpondwe followed. On 24 July, Uganda marked the needed 42 day period without any EVD cases to be declared Ebola-free. On 29 August, a 9-year-old Congolese girl became the fourth individual in Uganda to test positive for EVD when she crossed from the DRC into the district of Kasese . In regards to possible EVD cases in Tanzania, the WHO stated on 21 September 2019 that "to date, the clinical details and the results of the investigation, including laboratory tests performed for differential diagnosis of these patients, have not been shared with WHO. The insufficient information received by WHO does not allow for a formulation of a hypotheses regarding the possible cause of the illness". On 27 September, the CDC and U.S. State Department alerted potential travellers to the possibility of unreported EVD cases within Tanzania. The Tanzanian Health Minister Ummy Mwalimu stated on 3 October 2019 that there was no Ebola outbreak in Tanzania. The WHO were provided with a preparedness update on 18 October which outlined a range of actions, and included commentary that since the outbreak commenced, there had been "29 alerts of Ebola suspect cases reported, 17 samples tested and were negative for Ebola (including 2 in September 2019)". On 29 December, an American physician who was exposed to the Ebola virus (and who was non-symptomatic) was evacuated, and taken to the University of Nebraska Medical Center . On 12 January, the individual was released after 21 days without symptoms. The table which follows indicates confirmed , probable and suspected cases, as well as deaths ; the table also indicates the multiple countries where these cases took place, during this outbreak. # These figures may increase when new cases are discovered, and fall consequently, when tests show cases were not Ebola-related. †DRC Ministry of Public Health ‡ indicates suspected cases were not counted towards CFR x indicates 42 days have passed since the last case and outbreak is declared overAt the time of the epidemic, there were about 70 armed military groups, among them the Alliance of Patriots for a Free and Sovereign Congo and the Mai-Mayi Nduma défense du Congo-Rénové , in North Kivu. The fighting displaced thousands of individuals and seriously affected the response to the outbreak. According to the WHO, health care workers were to be accompanied by military personnel for protection and ring vaccination may not be possible. On 11 August 2018, it was reported that seven individuals were killed in Mayi-Moya due to a militant group, about 24 miles from the city of Beni where there were several EVD cases. On 24 August 2018, it was reported that an Ebola-stricken physician had been in contact with 97 individuals in an inaccessible military area, who hence could not be diagnosed. In September, it was reported that 2 peacekeepers were attacked and wounded by rebel groups in Beni, and 14 individuals were killed in a military attack. In September 2018, the WHO's Deputy Director-General for Emergency Preparedness and Response described the combination of military conflict and civilian distress as a potential "perfect storm" that could lead to a rapid worsening of the outbreak. On 20 October 2018, an armed rebel group in the DRC killed 13 civilians and took 12 children as hostages in Beni, which was then experiencing one of the worst outbreaks. On 11 November, six people were killed in an attack by an armed rebel group in Beni; as a consequence vaccinations were suspended there. Yet another attack reported on 17 November, in Beni by an armed rebel group forced the cessation of EVD containment efforts and WHO staff to evacuate to another DRC city for the time being. Beni continued to be the site of attacks by militant groups as 18 civilians were killed on 6 December. On 22 December, it was reported that elections for the President of the DRC would go forward despite the EVD outbreak, including in the Ebola-stricken area of Beni. Four days later, on 26 December, the DRC government reversed itself to indicate those Ebola-stricken areas, such as Beni, would not vote for several months; as a consequence election protesters ransacked an Ebola assessment center in Beni. Post election tensions continued when it was reported that the DRC government had cut off internet connectivity for the population, as the vote results were yet to be released. On 29 December 2018, Oxfam said it would suspend its work due to the ongoing violence in the DRC; on the same day, the International Rescue Committee suspended their Ebola support efforts as well. On 18 January, the African Union indicated that presidential election results announcements should be suspended in the DRC. The DRC Ministry of Public Health confirmed that the new Ebola outbreak was caused by the Zaire ebolavirus species – the same strain involved in the early 2018 outbreak in western DRC , but different genetic coding. The most lethal of the six known strains (including the newly discovered Bombali strain), Zaire ebolavirus strain is fatal in up to 90% of cases. Both Ebola and Marburg virus are part of the Filoviridae family, which is a virus family that causes severe hemorrhagic fever. The natural reservoir of the virus is thought to be the African fruit bat , which is used in many parts of Africa as bushmeat . A significant part of the actual EVD infection is based on immune suppression along with systemic inflammation, leading to multiple organ failure and shock . Systemic inflammation and fever may damage many types of tissues in the body but the consequences are especially profound in the liver where Ebola wipes out cells required to produce coagulation . In the gastrointestinal tract damaged cells lead to diarrhea putting patients at risk of dehydration. And in the adrenal gland the virus cripples the cells that make steroids which regulate blood pressure, resulting in circulatory collapse . Genetic epidemiology is a medical field that studies how genetic factors and the environment interact, in this case the outbreak affecting the populations of the Democratic Republic of the Congo and the neighboring country of Uganda. Genetic sequencing had already identified another unrelated strain of Zaire ebolavirus that was implicated in the 2018 outbreak in Équateur province which had ended only a week previously. This was the first time two epidemiologically and genetically distinct outbreaks of Ebola had emerged within weeks of each other. In 2020 a third outbreak of Zaire ebolavirus occurred in the DRC. Genome sequencing suggests that this outbreak – the 11th outbreak since the virus was first discovered in the country in 1976 – is related to neither the one in North Kivu Province nor the previous outbreak in the same area in 2018. A significant part of the actual EVD infection is based on immune suppression along with systemic inflammation, leading to multiple organ failure and shock . Systemic inflammation and fever may damage many types of tissues in the body but the consequences are especially profound in the liver where Ebola wipes out cells required to produce coagulation . In the gastrointestinal tract damaged cells lead to diarrhea putting patients at risk of dehydration. And in the adrenal gland the virus cripples the cells that make steroids which regulate blood pressure, resulting in circulatory collapse . Genetic epidemiology is a medical field that studies how genetic factors and the environment interact, in this case the outbreak affecting the populations of the Democratic Republic of the Congo and the neighboring country of Uganda. Genetic sequencing had already identified another unrelated strain of Zaire ebolavirus that was implicated in the 2018 outbreak in Équateur province which had ended only a week previously. This was the first time two epidemiologically and genetically distinct outbreaks of Ebola had emerged within weeks of each other. In 2020 a third outbreak of Zaire ebolavirus occurred in the DRC. Genome sequencing suggests that this outbreak – the 11th outbreak since the virus was first discovered in the country in 1976 – is related to neither the one in North Kivu Province nor the previous outbreak in the same area in 2018. Ebola virus is found in a variety of bodily fluids, such as breast milk, saliva, stool, blood, and semen, rendering it highly contagious due to ease of contact. Although a few transmission methods are known, there is a possibility that many other methods are unknown and must be further researched. Here are some potential routes of transmission: Droplets: Droplet transmission occurs when contact is made with virus-containing droplets. Fomites : Occurs when an individual comes in contact with a pathogen-containing surface. Bodily fluids: The most common way of transmitting the Ebola virus in humans is through contact with infected bodily fluids. Those infected by EVD generally gain immunity, although it is considered possible that such immunity is only temporary. On 31 October 2019, it was reported that an EVD survivor who had been assisting at a treatment center in Beni had been reinfected with EVD and died; such an incident was unprecedented. Even with the advances made in vaccine technology and treatment options during previous Ebola outbreaks, effective control of the North Kivu Epidemic continued to rely on traditional public health efforts including the timely identification and isolation of cases, control measures in hospital settings, identification and follow-up of contacts, community engagement, and safe burials. Data from the West African Ebola Outbreak showed that response strategies that achieved 60% efficacy for sanitary burial, case isolation, and contact-tracing combined, could have greatly reduced the daily number of Ebola cases and ended the outbreak after only 6 months. Contact tracing is defined as the identification and follow-up of persons who may have been in contact with a person infected with Ebola. Ideally, close contacts are observed for 21 days after their last known exposure to a case and isolated if they become symptomatic. The volume of contacts and the duration of monitoring presented challenges in Ebola surveillance as it required careful record-keeping by properly trained and equipped staff. To strengthen surveillance activities, the DRC Ministry of Health began disseminating standardized Ebola case definitions, developed reporting tools, and communication strategies, and began distribution of daily situation reports. Rapid response teams were deployed to affected health zones to strengthen Ebola case management and infection prevention and control in health care facilities and treatment centers. Similar to the West African Ebola Outbreak, relatively few (less than 10%) Ebola cases presented with hemorrhagic symptoms. In North Kivu and Ituri, outbreaks of sporadic violence and suspicion of the response in parts of some affected communities impacted heavily on disease surveillance. Poor record keeping by local health facilities also made it difficult or impossible to identify and trace contacts that might have been exposed to the disease while they were undergoing treatment for other illness at health centers. Additionally, the high degree of mobility of affected populations, combined with occasional mistrust of the response has meant that contacts that had been identified have sometimes been lost to follow-up for extended periods. Initially, it was estimated that 30-50% of contacts may not have originally been registered by contact tracing teams. Surveys among the affected population in North Kivu and Ituri showed both general mistrust with the Ebola response, partly related to years of mistrust of any governmental or external action, and specific opposition to the response because of conflicts with local cultural practices. Some of the cultural practices which complicated the Ebola response included eating bush meat, regular gatherings at family or village events, and traditional funeral practices, which were events that were particularly high risk for Ebola transmission. Additionally, people from the affected region reported that their perception of security and trust in the government, as well as humanitarian workers, declined over the course of the outbreak, complicating an already complex response. Combatting misinformation was a key element in overcoming Ebola in North Kivu. One study using surveys found that low institutional trust coupled with a belief in misinformation about Ebola were inversely associated with preventive behaviors in individuals, including Ebola vaccine acceptance. Belief in misinformation regarding Ebola was widespread, with 25% of respondents reporting that they did not believe the Ebola outbreak was real. Some of the rumors that were being circulated included statements that the outbreak did not exist, it was fabricated by the authorities for financial gains , or was fabricated to destabilize the region. Approximately 68% of respondents reported that they did not trust the local authorities to represent their interest, and community trust in the Ebola response was often further undermined by misinformation spread by local politicians. Early in the epidemic there were delays in patients seeking care for Ebola because the initial cases were misdiagnosed. Ebola symptoms were similar to symptoms of more common infectious diseases such as malaria, flu, and typhoid fever so patients would wait until their clinical situation deteriorated dangerously, usually after failure to respond to anti-malarial and/or antibiotic regimens, before reporting to the hospitals. The IFRC has called funerals "super-spreading events" as burial traditions include kissing and generally touching bodies. Safe burial teams formed by health workers are subject to suspicion. On 26 July 2019, it was reported that the country of Saudi Arabia would not allow visas from the DRC after the WHO declared it an international emergency due to EVD. On 1 August 2019, the country of Rwanda closed its border with the DRC after multiple cases in the city of Goma, which borders the country in the upper Northwestern region. To minimize the risk of the spread to neighboring countries, screening points which consisted of temperature and symptom monitoring were established at many border crossings. Over 2 million screenings were undertaken during the outbreak which no doubt contributed to the containment of the epidemic within DRC. Contact tracing is defined as the identification and follow-up of persons who may have been in contact with a person infected with Ebola. Ideally, close contacts are observed for 21 days after their last known exposure to a case and isolated if they become symptomatic. The volume of contacts and the duration of monitoring presented challenges in Ebola surveillance as it required careful record-keeping by properly trained and equipped staff. To strengthen surveillance activities, the DRC Ministry of Health began disseminating standardized Ebola case definitions, developed reporting tools, and communication strategies, and began distribution of daily situation reports. Rapid response teams were deployed to affected health zones to strengthen Ebola case management and infection prevention and control in health care facilities and treatment centers. Similar to the West African Ebola Outbreak, relatively few (less than 10%) Ebola cases presented with hemorrhagic symptoms. In North Kivu and Ituri, outbreaks of sporadic violence and suspicion of the response in parts of some affected communities impacted heavily on disease surveillance. Poor record keeping by local health facilities also made it difficult or impossible to identify and trace contacts that might have been exposed to the disease while they were undergoing treatment for other illness at health centers. Additionally, the high degree of mobility of affected populations, combined with occasional mistrust of the response has meant that contacts that had been identified have sometimes been lost to follow-up for extended periods. Initially, it was estimated that 30-50% of contacts may not have originally been registered by contact tracing teams. Surveys among the affected population in North Kivu and Ituri showed both general mistrust with the Ebola response, partly related to years of mistrust of any governmental or external action, and specific opposition to the response because of conflicts with local cultural practices. Some of the cultural practices which complicated the Ebola response included eating bush meat, regular gatherings at family or village events, and traditional funeral practices, which were events that were particularly high risk for Ebola transmission. Additionally, people from the affected region reported that their perception of security and trust in the government, as well as humanitarian workers, declined over the course of the outbreak, complicating an already complex response. Combatting misinformation was a key element in overcoming Ebola in North Kivu. One study using surveys found that low institutional trust coupled with a belief in misinformation about Ebola were inversely associated with preventive behaviors in individuals, including Ebola vaccine acceptance. Belief in misinformation regarding Ebola was widespread, with 25% of respondents reporting that they did not believe the Ebola outbreak was real. Some of the rumors that were being circulated included statements that the outbreak did not exist, it was fabricated by the authorities for financial gains , or was fabricated to destabilize the region. Approximately 68% of respondents reported that they did not trust the local authorities to represent their interest, and community trust in the Ebola response was often further undermined by misinformation spread by local politicians. Early in the epidemic there were delays in patients seeking care for Ebola because the initial cases were misdiagnosed. Ebola symptoms were similar to symptoms of more common infectious diseases such as malaria, flu, and typhoid fever so patients would wait until their clinical situation deteriorated dangerously, usually after failure to respond to anti-malarial and/or antibiotic regimens, before reporting to the hospitals. Combatting misinformation was a key element in overcoming Ebola in North Kivu. One study using surveys found that low institutional trust coupled with a belief in misinformation about Ebola were inversely associated with preventive behaviors in individuals, including Ebola vaccine acceptance. Belief in misinformation regarding Ebola was widespread, with 25% of respondents reporting that they did not believe the Ebola outbreak was real. Some of the rumors that were being circulated included statements that the outbreak did not exist, it was fabricated by the authorities for financial gains , or was fabricated to destabilize the region. Approximately 68% of respondents reported that they did not trust the local authorities to represent their interest, and community trust in the Ebola response was often further undermined by misinformation spread by local politicians. Early in the epidemic there were delays in patients seeking care for Ebola because the initial cases were misdiagnosed. Ebola symptoms were similar to symptoms of more common infectious diseases such as malaria, flu, and typhoid fever so patients would wait until their clinical situation deteriorated dangerously, usually after failure to respond to anti-malarial and/or antibiotic regimens, before reporting to the hospitals. The IFRC has called funerals "super-spreading events" as burial traditions include kissing and generally touching bodies. Safe burial teams formed by health workers are subject to suspicion. On 26 July 2019, it was reported that the country of Saudi Arabia would not allow visas from the DRC after the WHO declared it an international emergency due to EVD. On 1 August 2019, the country of Rwanda closed its border with the DRC after multiple cases in the city of Goma, which borders the country in the upper Northwestern region. To minimize the risk of the spread to neighboring countries, screening points which consisted of temperature and symptom monitoring were established at many border crossings. Over 2 million screenings were undertaken during the outbreak which no doubt contributed to the containment of the epidemic within DRC. In August 2018, the WHO evaluated several drugs used to treat EVD, including Remdesivir , ZMapp , atoltivimab/maftivimab/odesivimab , ansuvimab and favipiravir . The drug ansuvimab (which is a monoclonal antibody ) was deployed for the first time to treat infected individuals during this EVD outbreak. In November 2018, the DRC gave approval to start randomized clinical trials for EVD treatment. On 12 August 2019, it was announced that two clinical trial medications were found to improve the rate of survival in those infected by EVD: atoltivimab/maftivimab/odesivimab, a cocktail of three monoclonal Ebola antibodies, and ansuvimab. These two will be further used in therapy; when used shortly after infection they were found to have a 90% survival rate. ZMapp and Remdesivir were subsequently discontinued. In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab with an indication for the treatment of infection caused by Zaire ebolavirus . On 8 August 2018, the process of vaccination began with rVSV-ZEBOV Ebola vaccine . While several studies have shown the vaccine to be safe and protective against the virus, additional research is needed before it can be licensed. Consequently, the WHO reported that it was being used under a ring vaccination strategy with what is known as " compassionate use " to protect persons at highest risk of the Ebola outbreak, i.e. contacts of those infected, contacts of those contacts, and front-line medical personnel. As of 15 September, according to the WHO, almost a quarter of a million individuals had been vaccinated in the outbreak. On 20 September 2019 it was reported that a second vaccine by Johnson & Johnson would be introduced in the current EVD epidemic in the DRC. In November 2019, the World Health Organization prequalified an Ebola vaccine, rVSV-ZEBOV, for the first time. As of 22 February 2020, a total of 297,275 people had been vaccinated since the start of the outbreak. By 21 June 2020, 303,905 people had been vaccinated with rVSV-ZEBOV and 20,339 were given the initial dose of Ad26-ZEBOV/MVA-BN-FILO. Vaccination has helped to contain the epidemic, though military attacks and community resistance have complicated distribution of the vaccines. Based on a lack of evidence about the safety of the vaccine during pregnancy, the DRC ministry of health and the WHO decided to cease vaccinating women who were pregnant or lactating. Some authorities criticized this decision as ethically "utterly indefensible". They noted that as caregivers of the sick, pregnant and lactating women are more likely to contract Ebola. They also noted that since it is known that almost 100% of pregnant women who contract Ebola will die, a safety concern should not be a deciding factor. As of June 2019, pregnant and lactating women were also being vaccinated. The DRC Ministry of Public Health reported on 16 August 2018 that 316 individuals had been vaccinated. On 24 August, the DRC indicated it had vaccinated 2,957 individuals, including 1,422 in Mabalako against the Ebola virus. By late October, more than 20,000 individuals had been vaccinated. In December, Dr. Peter Salama, who is Deputy Director-General of Emergency Preparedness and Response for WHO, reported that the current 300,000 vaccine stockpile might not be enough to contain the EVD outbreak, especially since it takes several months to make more of the Zaire EVD vaccine (rVSV-ZEBOV). On 11 December, it was reported that Beni only had 4,290 doses of vaccine in stock. As of August 2019, Merck & Co , the producers of the vaccine in use, reported a stockpile sufficient for 500,000 individuals, with more in production. In April 2019, the WHO published the preliminary results of its research, in association with the DRC's Institut National pour la Recherche Biomedicale , into the effectiveness of the ring vaccination program, including data from 93,965 at-risk people who had been vaccinated. WHO stated that the rVSV-ZEBOV-GP vaccine had been 97.5% effective at stopping Ebola transmission. The vaccine had also reduced mortality among those who were infected after vaccination. The ring vaccination strategy was effective at reducing EVD in contacts of contacts (tertiary cases), with only two such cases being reported. In August 2018, the Mangina Ebola Treatment Center was reported to be operational. A fourth Ebola Treatment Center (after those in Mangina, Beni and Butembo ) was inaugurated in September in Makeke in the Mandima Health Zone of Ituri Province . Makeke is less than five kilometers from Mangina along a well-traveled local road; the site had been proposed in August when it appeared that a second Ebola Treatment Center would be needed in the area, and space was insufficient in Mangina itself to accommodate one. By mid-September, however, there had been only two additional cases in the Mandima Health Zone, and only sporadic cases were being reported in the Mabalako Health Zone. In February 2019, it was reported that attacks at treatment centers had been carried out in Butembo and Katwa. The motives behind the attacks were unclear. Due to the violence, international aid organizations had to stop their work in the two communities. In April, an epidemiologist from WHO was killed and two health workers injured in a militia attack on Butembo University Hospital in Katwa. In May, WHO's health emergencies chief said insecurity had become a "major impediment" to controlling the outbreak. He reported that since January there had been 42 attacks on health facilities and 85 health workers had been wounded or killed. "Every time we have managed to regain control over the virus and contain its spread, we have suffered major, major security events. We are anticipating a scenario of continued intense transmission". Health workers must wear personal protection equipment during treatment of those affected by the virus. On 3 September 2018, WHO stated that 16 health workers had contracted the virus. On 10 December, the WHO reported that the current DRC outbreak had led to 49 healthcare workers contracting the Ebola virus, and 15 had died. As of 30 April 2019, there have been 92 health care workers in the DRC infected with EVD, of which 33 had died. With false rumors being spread by word-of-mouth and social media, residents remain mistrustful and fearful of health care workers. In January 2020, it was reported that there had been nearly 400 attacks on medical workers since the outbreak began in 2018. On 8 August 2018, the process of vaccination began with rVSV-ZEBOV Ebola vaccine . While several studies have shown the vaccine to be safe and protective against the virus, additional research is needed before it can be licensed. Consequently, the WHO reported that it was being used under a ring vaccination strategy with what is known as " compassionate use " to protect persons at highest risk of the Ebola outbreak, i.e. contacts of those infected, contacts of those contacts, and front-line medical personnel. As of 15 September, according to the WHO, almost a quarter of a million individuals had been vaccinated in the outbreak. On 20 September 2019 it was reported that a second vaccine by Johnson & Johnson would be introduced in the current EVD epidemic in the DRC. In November 2019, the World Health Organization prequalified an Ebola vaccine, rVSV-ZEBOV, for the first time. As of 22 February 2020, a total of 297,275 people had been vaccinated since the start of the outbreak. By 21 June 2020, 303,905 people had been vaccinated with rVSV-ZEBOV and 20,339 were given the initial dose of Ad26-ZEBOV/MVA-BN-FILO. Vaccination has helped to contain the epidemic, though military attacks and community resistance have complicated distribution of the vaccines. Based on a lack of evidence about the safety of the vaccine during pregnancy, the DRC ministry of health and the WHO decided to cease vaccinating women who were pregnant or lactating. Some authorities criticized this decision as ethically "utterly indefensible". They noted that as caregivers of the sick, pregnant and lactating women are more likely to contract Ebola. They also noted that since it is known that almost 100% of pregnant women who contract Ebola will die, a safety concern should not be a deciding factor. As of June 2019, pregnant and lactating women were also being vaccinated. The DRC Ministry of Public Health reported on 16 August 2018 that 316 individuals had been vaccinated. On 24 August, the DRC indicated it had vaccinated 2,957 individuals, including 1,422 in Mabalako against the Ebola virus. By late October, more than 20,000 individuals had been vaccinated. In December, Dr. Peter Salama, who is Deputy Director-General of Emergency Preparedness and Response for WHO, reported that the current 300,000 vaccine stockpile might not be enough to contain the EVD outbreak, especially since it takes several months to make more of the Zaire EVD vaccine (rVSV-ZEBOV). On 11 December, it was reported that Beni only had 4,290 doses of vaccine in stock. As of August 2019, Merck & Co , the producers of the vaccine in use, reported a stockpile sufficient for 500,000 individuals, with more in production. In April 2019, the WHO published the preliminary results of its research, in association with the DRC's Institut National pour la Recherche Biomedicale , into the effectiveness of the ring vaccination program, including data from 93,965 at-risk people who had been vaccinated. WHO stated that the rVSV-ZEBOV-GP vaccine had been 97.5% effective at stopping Ebola transmission. The vaccine had also reduced mortality among those who were infected after vaccination. The ring vaccination strategy was effective at reducing EVD in contacts of contacts (tertiary cases), with only two such cases being reported. Based on a lack of evidence about the safety of the vaccine during pregnancy, the DRC ministry of health and the WHO decided to cease vaccinating women who were pregnant or lactating. Some authorities criticized this decision as ethically "utterly indefensible". They noted that as caregivers of the sick, pregnant and lactating women are more likely to contract Ebola. They also noted that since it is known that almost 100% of pregnant women who contract Ebola will die, a safety concern should not be a deciding factor. As of June 2019, pregnant and lactating women were also being vaccinated. The DRC Ministry of Public Health reported on 16 August 2018 that 316 individuals had been vaccinated. On 24 August, the DRC indicated it had vaccinated 2,957 individuals, including 1,422 in Mabalako against the Ebola virus. By late October, more than 20,000 individuals had been vaccinated. In December, Dr. Peter Salama, who is Deputy Director-General of Emergency Preparedness and Response for WHO, reported that the current 300,000 vaccine stockpile might not be enough to contain the EVD outbreak, especially since it takes several months to make more of the Zaire EVD vaccine (rVSV-ZEBOV). On 11 December, it was reported that Beni only had 4,290 doses of vaccine in stock. As of August 2019, Merck & Co , the producers of the vaccine in use, reported a stockpile sufficient for 500,000 individuals, with more in production. In April 2019, the WHO published the preliminary results of its research, in association with the DRC's Institut National pour la Recherche Biomedicale , into the effectiveness of the ring vaccination program, including data from 93,965 at-risk people who had been vaccinated. WHO stated that the rVSV-ZEBOV-GP vaccine had been 97.5% effective at stopping Ebola transmission. The vaccine had also reduced mortality among those who were infected after vaccination. The ring vaccination strategy was effective at reducing EVD in contacts of contacts (tertiary cases), with only two such cases being reported. In August 2018, the Mangina Ebola Treatment Center was reported to be operational. A fourth Ebola Treatment Center (after those in Mangina, Beni and Butembo ) was inaugurated in September in Makeke in the Mandima Health Zone of Ituri Province . Makeke is less than five kilometers from Mangina along a well-traveled local road; the site had been proposed in August when it appeared that a second Ebola Treatment Center would be needed in the area, and space was insufficient in Mangina itself to accommodate one. By mid-September, however, there had been only two additional cases in the Mandima Health Zone, and only sporadic cases were being reported in the Mabalako Health Zone. In February 2019, it was reported that attacks at treatment centers had been carried out in Butembo and Katwa. The motives behind the attacks were unclear. Due to the violence, international aid organizations had to stop their work in the two communities. In April, an epidemiologist from WHO was killed and two health workers injured in a militia attack on Butembo University Hospital in Katwa. In May, WHO's health emergencies chief said insecurity had become a "major impediment" to controlling the outbreak. He reported that since January there had been 42 attacks on health facilities and 85 health workers had been wounded or killed. "Every time we have managed to regain control over the virus and contain its spread, we have suffered major, major security events. We are anticipating a scenario of continued intense transmission". Health workers must wear personal protection equipment during treatment of those affected by the virus. On 3 September 2018, WHO stated that 16 health workers had contracted the virus. On 10 December, the WHO reported that the current DRC outbreak had led to 49 healthcare workers contracting the Ebola virus, and 15 had died. As of 30 April 2019, there have been 92 health care workers in the DRC infected with EVD, of which 33 had died. With false rumors being spread by word-of-mouth and social media, residents remain mistrustful and fearful of health care workers. In January 2020, it was reported that there had been nearly 400 attacks on medical workers since the outbreak began in 2018. Health workers must wear personal protection equipment during treatment of those affected by the virus. On 3 September 2018, WHO stated that 16 health workers had contracted the virus. On 10 December, the WHO reported that the current DRC outbreak had led to 49 healthcare workers contracting the Ebola virus, and 15 had died. As of 30 April 2019, there have been 92 health care workers in the DRC infected with EVD, of which 33 had died. With false rumors being spread by word-of-mouth and social media, residents remain mistrustful and fearful of health care workers. In January 2020, it was reported that there had been nearly 400 attacks on medical workers since the outbreak began in 2018. In terms of prognosis, aside from the possible effects of post-Ebola syndrome , there is also the reality of survivors returning to communities where they might be shunned due to the fear many have towards the Ebola virus, hence psychosocial assistance is needed. Many survivors of EVD face serious side effects, including but not limited to the following: The Ebola virus disease outbreak in Zaire (Yambuku) started in late 1976, and was the second outbreak ever after the earlier one in Sudan the same year. On 1 August 2018, the tenth Ebola outbreak was declared in the DRC, only a few days after a prior outbreak in the same country had been declared over on 24 July. Learning from other responses, such as in the 2000 outbreak in Uganda , the WHO established its Global Outbreak Alert and Response Network , and other public health measures were instituted in areas at high risk. Field laboratories were established to confirm cases, instead of shipping samples to South Africa . Additionally, the outbreak was closely monitored by the CDC Special Pathogens Branch. One way to measure the outbreak is via the basic reproduction number , R 0 , a statistical measure of the average number of people expected to be infected by one person with a disease. If the basic reproduction number is less than 1, the infection dies out; if it is greater than 1, the infection continues to spread—with exponential growth in the number of cases. A March 2019 paper by Tariq et al. suggested that R 0 was oscillating around 0.9. During the Ebola outbreak in Democratic Republic of the Congo, a number of organizations helped in different capacities: CARITAS DRC, CARE International , Cooperazione Internationale (COOPE), Catholic Organization for Relief and Development Aid (CORDAID/PAP-DRC), International Rescue Committee (IRC), Médecins Sans Frontières (MSF), Oxfam , International Federation of Red Cross and Red Crescent Societies (IFRC), International Committee of the Red Cross (ICRC), and Samaritan's Purse . On 12 April 2019, the WHO Emergency Committee was reconvened by the WHO Director-General after an increase in the rate of new cases, and determined that the outbreak still failed to meet the criteria for a Public Health Emergency of International Concern (PHEIC). Following the confirmation of Ebola crossing into Uganda, a third review by the WHO on 14 June 2019 concluded that while the outbreak was a health emergency in the DRC and the region, it did not meet all three criteria required for a PHEIC. Following a case in Goma, the reconvening of a fourth review was announced on 15 July 2019. The WHO officially declared the situation a PHEIC on 17 July 2019, and as of 12 February 2020, it continues to be a PHEIC. In September 2021, a commission found that between 2018 and 2020, WHO staff had engaged in sex abuse and rape. The report prompted WHO's chief Tedros Adhanom to issue a formal apology to those women and girls affected. The World Bank was criticised when its Pandemic Emergency Financing Facility , intended to support countries affected by pandemic diseases, had only paid out $31 million of a potential total of $425 million by August 2019 while generating substantial returns for investors. The conditions used to decide when the fund should pay out to disease-affected countries were criticised as too stringent. Financial support has been contributed by the governments of the US and the UK, among others. The UK DfID minister, Rory Stewart , visited the area in July 2019, and called for other western countries, including Canada , France and Germany , to donate more financial aid. He identified a funding deficit of $100–300 million to continue responding to the outbreak until December. He urged WHO to classify the situation as a PHEIC, to facilitate the release of international aid. On 12 April 2019, the WHO Emergency Committee was reconvened by the WHO Director-General after an increase in the rate of new cases, and determined that the outbreak still failed to meet the criteria for a Public Health Emergency of International Concern (PHEIC). Following the confirmation of Ebola crossing into Uganda, a third review by the WHO on 14 June 2019 concluded that while the outbreak was a health emergency in the DRC and the region, it did not meet all three criteria required for a PHEIC. Following a case in Goma, the reconvening of a fourth review was announced on 15 July 2019. The WHO officially declared the situation a PHEIC on 17 July 2019, and as of 12 February 2020, it continues to be a PHEIC. In September 2021, a commission found that between 2018 and 2020, WHO staff had engaged in sex abuse and rape. The report prompted WHO's chief Tedros Adhanom to issue a formal apology to those women and girls affected. In September 2021, a commission found that between 2018 and 2020, WHO staff had engaged in sex abuse and rape. The report prompted WHO's chief Tedros Adhanom to issue a formal apology to those women and girls affected. The World Bank was criticised when its Pandemic Emergency Financing Facility , intended to support countries affected by pandemic diseases, had only paid out $31 million of a potential total of $425 million by August 2019 while generating substantial returns for investors. The conditions used to decide when the fund should pay out to disease-affected countries were criticised as too stringent. Financial support has been contributed by the governments of the US and the UK, among others. The UK DfID minister, Rory Stewart , visited the area in July 2019, and called for other western countries, including Canada , France and Germany , to donate more financial aid. He identified a funding deficit of $100–300 million to continue responding to the outbreak until December. He urged WHO to classify the situation as a PHEIC, to facilitate the release of international aid. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. This area was the site of the 2018 Équateur province Ebola outbreak , which infected 53 people and resulted in 29 deaths. That outbreak was quickly brought under control with the use of the Ebola vaccine. Genome sequencing suggested that this 2020 outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, was unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified with four fatalities. It was expected that more people would be identified as surveillance activities increased. The WHO assisted with the response to this outbreak in part using the structures put in place for the 2018 outbreak. Testing and contact tracing was used and additional medical staff had been sent in. Médecins Sans Frontières was also on hand to give assistance if needed. The outbreak added to an already difficult time for the Congo due to both COVID-19 cases and a large measles outbreak that has caused more than 7,000 deaths as of August 2020. By 8 June, a total of 12 cases had been identified in and around Mbandaka and 6 deaths due to the virus. The WHO said 300 people in Mbandaka and the surrounding Équateur province had been vaccinated. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. On 17 October, it had increased to 128 cases and 53 deaths, despite an effective vaccine being available. As of 18 November, the World Health Organization has had no reported cases of Ebola in Équateur province for 42 days; therefore the outbreak is over. In the end there were 130 cases and 55 dead due to the virus. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. This area was the site of the 2018 Équateur province Ebola outbreak , which infected 53 people and resulted in 29 deaths. That outbreak was quickly brought under control with the use of the Ebola vaccine. Genome sequencing suggested that this 2020 outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, was unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified with four fatalities. It was expected that more people would be identified as surveillance activities increased. The WHO assisted with the response to this outbreak in part using the structures put in place for the 2018 outbreak. Testing and contact tracing was used and additional medical staff had been sent in. Médecins Sans Frontières was also on hand to give assistance if needed. The outbreak added to an already difficult time for the Congo due to both COVID-19 cases and a large measles outbreak that has caused more than 7,000 deaths as of August 2020. By 8 June, a total of 12 cases had been identified in and around Mbandaka and 6 deaths due to the virus. The WHO said 300 people in Mbandaka and the surrounding Équateur province had been vaccinated. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. On 17 October, it had increased to 128 cases and 53 deaths, despite an effective vaccine being available. As of 18 November, the World Health Organization has had no reported cases of Ebola in Équateur province for 42 days; therefore the outbreak is over. In the end there were 130 cases and 55 dead due to the virus.

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Crimean-Congo haemorrhagic fever

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Tick-borne disease

Tick-borne diseases , which afflict humans and other animals, are caused by infectious agents transmitted by tick bites. They are caused by infection with a variety of pathogens , including rickettsia and other types of bacteria , viruses , and protozoa . The economic impact of tick-borne diseases is considered to be substantial in humans, and tick-borne diseases are estimated to affect ~80 % of cattle worldwide. Most of these pathogens require passage through vertebrate hosts as part of their life cycle. Tick-borne infections in humans, farm animals, and companion animals are primarily associated with wildlife animal reservoirs. Many tick-borne infections in humans involve a complex cycle between wildlife animal reservoirs and tick vectors. The survival and transmission of these tick-borne viruses are closely linked to their interactions with tick vectors and host cells. These viruses are classified into different families, including Asfarviridae , Reoviridae , Rhabdoviridae , Orthomyxoviridae , Bunyaviridae , and Flaviviridae . The occurrence of ticks and tick-borne illnesses in humans is increasing. Tick populations are spreading into new areas, in part due to climate change . Tick populations are also affected by changes in the populations of their hosts (e.g. deer, cattle, mice, lizards) and those hosts' predators (e.g. foxes). Diversity and availability of hosts and predators can be affected by deforestation and habitat fragmentation . Because individual ticks can harbor more than one disease-causing agent, patients can be infected with more than one pathogen at the same time, compounding the difficulty in diagnosis and treatment. As the incidence of tick-borne illnesses increases and the geographic areas in which they are found expand, health workers increasingly must be able to distinguish the diverse, and often overlapping, clinical presentations of these diseases. As of 2020 [ update ] 18 tick-borne pathogens have been identified in the United States according to the Centers for Disease Control and at least 27 are known globally. New tick-borne diseases have been discovered in the 21st century, due in part to the use of molecular assays and next-generation sequencing . Ticks tend to be more active during warmer months, though this varies by geographic region and climate. Areas with woods, bushes, high grass, or leaf litter are likely to have more ticks. Those bitten commonly experience symptoms such as body aches, fever , fatigue , joint pain , or rashes . People can limit their exposure to tick bites by wearing light-colored clothing (including pants and long sleeves), using insect repellent with 20%–30% N,N-Diethyl-3-methylbenzamide (DEET) , tucking their pants legs into their socks, checking for ticks frequently, and washing and drying their clothing in a hot dryer. According to the World Health Organization , tick-to-animal transmission is difficult to prevent because animals do not show visible symptoms; the only effective prevention relies on killing ticks on the livestock production facility. Ticks also have the potential to induce a motor illness characterized by acute, ascending flaccid paralysis. This condition can be fatal if not treated promptly, affecting both humans and animals. It is mainly associated with certain species of ticks. Symptoms typically ranges from fatigue, numbness in the legs, muscle aches, and, to in some cases, paralysis and other severe neurological manifestations. Tick-borne diseases (TBD) are a major health threat in the US. The number of pathogens and the burden of disease have been increasing over the last couple decades. With improved diagnostics and surveillance, new pathogens are regularly identified, bettering our understanding of TBDs. Unfortunately, diagnosis of these illnesses remains a challenge, with many TBDs presenting with similar nonspecific symptoms and diagnosis requiring a battery of assays to assess patients adequately. New advanced molecular diagnostic methods, including next-generation sequencing and metagenomics analysis, promise improved detection of novel and emerging pathogens with the ability to detect a litany of potential pathogens with a single assay. Ticks should be removed as soon as safely possible once discovered. They can be removed either by grasping tweezers as close to the mouth as possible and pulling without rotation; some companies market grooved tools that rotate the hypostome to facilitate removal. Chemical methods to make the tick self-detach, or trying to pull the tick out with one's fingers, are not efficient methods. In Australia and New Zealand, where tick-borne infections are less common than tick reactions, the Australasian Society of Clinical Immunology and Allergy recommends seeking medical assistance or killing ticks in-situ by freezing and then leaving them to fall out to prevent allergic/anaphylactic reactions. Ticks tend to be more active during warmer months, though this varies by geographic region and climate. Areas with woods, bushes, high grass, or leaf litter are likely to have more ticks. Those bitten commonly experience symptoms such as body aches, fever , fatigue , joint pain , or rashes . People can limit their exposure to tick bites by wearing light-colored clothing (including pants and long sleeves), using insect repellent with 20%–30% N,N-Diethyl-3-methylbenzamide (DEET) , tucking their pants legs into their socks, checking for ticks frequently, and washing and drying their clothing in a hot dryer. According to the World Health Organization , tick-to-animal transmission is difficult to prevent because animals do not show visible symptoms; the only effective prevention relies on killing ticks on the livestock production facility. Ticks also have the potential to induce a motor illness characterized by acute, ascending flaccid paralysis. This condition can be fatal if not treated promptly, affecting both humans and animals. It is mainly associated with certain species of ticks. Symptoms typically ranges from fatigue, numbness in the legs, muscle aches, and, to in some cases, paralysis and other severe neurological manifestations. Tick-borne diseases (TBD) are a major health threat in the US. The number of pathogens and the burden of disease have been increasing over the last couple decades. With improved diagnostics and surveillance, new pathogens are regularly identified, bettering our understanding of TBDs. Unfortunately, diagnosis of these illnesses remains a challenge, with many TBDs presenting with similar nonspecific symptoms and diagnosis requiring a battery of assays to assess patients adequately. New advanced molecular diagnostic methods, including next-generation sequencing and metagenomics analysis, promise improved detection of novel and emerging pathogens with the ability to detect a litany of potential pathogens with a single assay. Ticks should be removed as soon as safely possible once discovered. They can be removed either by grasping tweezers as close to the mouth as possible and pulling without rotation; some companies market grooved tools that rotate the hypostome to facilitate removal. Chemical methods to make the tick self-detach, or trying to pull the tick out with one's fingers, are not efficient methods. In Australia and New Zealand, where tick-borne infections are less common than tick reactions, the Australasian Society of Clinical Immunology and Allergy recommends seeking medical assistance or killing ticks in-situ by freezing and then leaving them to fall out to prevent allergic/anaphylactic reactions. Diagnosing tick-borne diseases involves a dual approach. Some diagnoses rely on clinical observations and symptom analysis, while others are confirmed through laboratory tests. ticks can transmit a wide range of viruses, many of which are arboviruses. In general, specific laboratory tests are not available for rapid diagnosis of tick-borne diseases. Due to their seriousness, antibiotic treatment is often justified based on clinical presentation alone. Diagnosing Lyme borreliosis relies on clinical criteria, with a history of a tick bite and associated symptoms being crucial. Laboratory diagnosis follows a 'two-tiered diagnostic protocol,' involving detecting specific antibodies using methods such as immunoenzymatic assays and Western blot tests, preferably with recombinant antigens. While ELISA and Western blot have similar sensitivity, Western blot is more specific due to the identification of specific immunoreactive bands. Seroconversion typically occurs around two weeks after symptom onset, but false positive ELISA results can be linked to poorly reactive antibodies against specific antigens, especially in patients with other infectious and non-infectious diseases. Tick-borne encephalitis (TBE) presents non-specific clinical features, making laboratory diagnosis crucial. The diagnostic process typically involves identifying specific IgM- and IgG-serum antibodies through enzyme-linked immunosorbent assay (ELISA) since these antibodies are detectable in most cases upon hospitalization. Patients with Lyme disease who are treated with appropriate antibiotics usually recover rapidly and completely. Antibiotics commonly used include doxycycline, amoxicillin, or cefuroxime axetil. For Anaplasmosis , ehrlichiosis and Rocky Mountain spotted fever, Doxycycline is the first line treatment for adults and children of all ages. For babesiosis, a combination therapy with atovaquone and azithromycin is most commonly recommended for treatment of mild to moderate babesiosis. Treatment is usually continued for 7 to 10 days. A combination regimen of oral clindamycin and quinine has also been proven effective, but the rate of adverse reactions is significantly higher with this combination. For Powassan virus, there are no medications for treating Powassan virus infections. Medications, however, can help to relieve symptoms and prevent complications. People with severe disease are typically treated in a hospital where they may be given intravenous fluids, fever-reducing medications, breathing support, and other therapies as needed. For a person or pet to acquire a tick-borne disease requires that the individual gets bitten by a tick and that the tick feeds for a sufficient period of time. The feeding time required to transmit pathogens differs for different ticks and different pathogens. Transmission of the bacterium that causes Lyme disease is well understood to require a substantial feeding period. In general, soft ticks ( Argasidae ) transmit pathogens within minutes of attachment because they feed more frequently, whereas hard ticks ( Ixodidae ) take hours or days, but the latter are more common and harder to remove. For an individual to acquire infection, the feeding tick must also be infected. Not all ticks are infected. In most places in the US, 30-50% of deer ticks will be infected with Borrelia burgdorferi (the agent of Lyme disease). Other pathogens are much more rare. Ticks can be tested for infection using a highly specific and sensitive qPCR procedure. Several commercial labs provide this service to individuals for a fee. The Laboratory of Medical Zoology (LMZ), a nonprofit lab at the University of Massachusetts , provides a comprehensive TickReport for a variety of human pathogens and makes the data available to the public. Those wishing to know the incidence of tick-borne diseases in their town or state can search the LMZ surveillance database. Major tick-borne diseases include: Organism: Francisella tularensis , A. americanum Vector: D. variabilis , D. andersoni Region (US): Southeast, South-central, West, widespread Organism: Cytauxzoon felis Vector: Amblyomma americanum (Lone star tick) Region (US): South, SoutheastOrganism: Francisella tularensis , A. americanum Vector: D. variabilis , D. andersoni Region (US): Southeast, South-central, West, widespreadOrganism: Cytauxzoon felis Vector: Amblyomma americanum (Lone star tick) Region (US): South, Southeast

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Crimean-Congo haemorrhagic fever

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Research Centre for Emerging and Reemerging Infectious Diseases

The Research Centre for Emerging and Reemerging Infectious Diseases is part of the Pasteur Institute of Iran . [ citation needed ] It is the National Reference Laboratory for Plague , Tularemia , and Q Fever . [ clarification needed ]One year after World War I and despite the persistent problems caused by casualties and infectious diseases in the country resulting from war, the Iranian government decided to renew its relationship with France to promote medical sciences and research concerning different types of endemic infectious diseases . The Iranian delegates met Pierre Paul Émile Roux , the general director of the Pasteur Institute of Paris, in 1919 and this visit laid the foundation of Pasteur Institute of Iran. On 20 January 1921, Professor René Legroux, the leading delegate of the Pasteur Institute of Paris, signed a memorandum of understanding with the minister for foreign affairs of Iran and as a result, Pasteur Institute of Iran was established. Pasteur Institute of Iran was the tenth Pasteur Institute formed worldwide. Moreover, Pasteur Institute of Iran formally started its activity on 23 August 1921. Due to World War II , the relationship between the Pasteur Institutes in Iran and Paris was interrupted (from 1939 to 1945). Before the war, when the number of laboratories was limited and their activities failed to meet the needs of the country, most of the national health issues related to the ministry of health were addressed by Pasteur Institute of Iran.Iranian physicians were familiar with the human plague for a long time. Although there is little information about the situation of plague from earlier centuries, we have more documented evidence from the 19th and 20th centuries. During the Qajar dynasty (1895 to 1925), cholera and plague were the most frequently documented outbreaks. Such lethal diseases were not hard to imagine considering the poor hygiene and lack of knowledge about the root of transmission, prevention and effective treatment of that time. Several plague outbreaks took place during the Qajar dynasty in Iran. In 1871, a severe form of plague outbreak happened in Saghez and Bane (two cities in Kurdistan province ) and the Iranian and non-Iranian physicians, such as Dr. Johan Louis Schlimmer, the instructor in the Darolfonun School, were appointed to control this disease. Dr. Schlimmer noted his observations in his book, "Schlimmer's Terminology ", published in 1874. The first Iranian physician who registered his observations about plague using modern medical science was Mohammad Razi Tabatabai, the senior physician in Naser al-Din Shah's army; his book was published under the title "Plague" in 1875. Dr. Joseph Desire Tholozan, (1820 to 1897), the royal physician of Naser Al-din Shah and the head of the ministry of health at that time, evaluated the main and natural foci of plague in Kurdistan between 1870 and 1882 and found certain foci for the disease in various villages of that area. In 1946, together with the new program of activities of Pasteur Institute of Iran, the epidemiology department of Pasteur Institute of Iran started its activities under the supervision of Dr. Baltazard, the general director of the institute. They started their mission in Northwest of Iran and attempted to prepare an epidemiological map of infectious diseases of the country using a portable laboratory in a truck. It later became more practical after they were equipped with professional cars. Although Kurdistan had a history of plague, it was due to the plague outbreak in Kurdistan in the same year that for the first time the research teams were dispatched to an area in which they could control the outbreak via quarantining the foci and epidemiological procedures on the humans and rodents. Studies of the plague foci in this region and the importance of this disease motivated Dr. Baltazard, Dr. Shamsa, Dr. Karimi, Dr. Habibi, Dr. Bahmanyar, Dr. Agha Eftekhari, Dr. Farhang Azad, Dr. Seyyedian and Dr. Majd Teymouri to conduct extensive scientific and epidemiologic studies after educating expert technicians and providing sufficient facilities. During the nine plague outbreaks in Kurdistan and Azerbaijan between 1946 and 1965, many infected people survived from the disease by the efforts of the dispatched teams of Pasteur Institute of Iran; however, 156 died. In 1952, the first plague laboratory was founded in Akanlu village, near the epicenter of plague in Kurdistan, Iran, on a piece of land bestowed by Manuchehr Gharagozlou, an Iranian friend of Dr. Baltazard. At this research center, currently called "The Research Center for Emerging and Reemerging infectious diseases", Dr. Baltazard and his perseverant colleagues conducted extensive research on plague and established this center as one of the international references for plague. Since 1952, research teams could base themselves in the area for months at a time and conduct detailed research on rodents under more favorable conditions. They were no longer required to carry their equipment throughout their missions. During those years, the integration of field and laboratory collaborations was a key to effective epidemiological actions and led to great research hypotheses. The extensive research by the teams of Pasteur Institute of Iran showed that rodents of the two types Meriones Persicus and Meriones libycus were the main natural reservoirs, unlike their resistance to plague; accordingly, they first proposed that the main reservoir of a disease should be sought amongst the most resistant, not the most sensitive, and such a theory is now accepted as a scientific fact. They also presented their scientific qualifications by publishing several scientific articles. During the development of this research center, many international scientists visited the center, lecturing, studying and/or researching in their fields. In particular, Dr. Xavier Misonne, a Belgian rodentologist who investigated rodent life in Iran and Dr. Jean Marie Klein, an entomologist, who conducted extensive research on fleas in the Akanlu center, played important roles. In addition, the aerial photographs of Kurdistan and Hamadan were obtained from Iran's army and rodents' locations and the infection were mapped and reported and the first foundations of GIS were set. The research team carefully concentrated on the epizootic trend of the region. The achievements of Pasteur Institute of Iran regarding plague research attracted global attention and such a success motivated them to assign Iranians international plague research. The experts and researchers of Pasteur Institute of Iran, known as WHO experts, continued to conduct related research in many neighboring countries such as Turkey, Syria, Iraq and Yemen, Southeast Asia (India, Indonesia, Thailand), Burma, Brazil, and Africa (Zaire, Tanzania); they published all of their research results to be used by others. Most of this research was financially supported by WHO. In 1972, a WHO meeting on plague was held in this center with many participants from all over the world. Although Dr. Baltazard left Iran in 1962, plague studies continued to be conducted in the following years in such a way that in 1978 a new focus of the disease was reported in the Sarab region in Eastern Azerbaijan by Dr. Yunos Karimi and his colleagues. Pasteur Institute of Iran has been designated to manage the infectious disease situation in Iran and when taking into account all its completed projects, the Research Center for Emerging and Reemerging infectious diseases can be regarded as the pioneer center for field epidemiology in Iran. The Epidemiology Department of Pasteur Institute of Iran and the Akanlu Research Center did researches on tularemia, recurrent fever, rabies and animal bites in addition to plague studies, the main research field of this center. In addition to close collaborations with other departments of the institute such as parasitology and rabies, the epidemiology department and Akanlu Research Center has conducted research in other fields such as hemorrhagic fevers, malaria, cholera and smallpox. TOne of the other research fields of the Research Center for Emerging and Reemerging infectious diseases has been running researches on tularemia in Iran. Great research by Dr. Shamsa and his colleagues led to the first report of this disease among the domestic livestock and wildlife in Northwest and Eastern Iran. In this study, more than 4500 wild mammals, 200 sheep and cows were traced for the causative agent of tularemia in 47 locations in Iran. As a result, this study greatly contributed to the identification of wild mammals acting as reservoirs for many zoonotic diseases around the country. The studies about the epidemiology of tularemia continued in the years thereafter as well. The first report of a human case of tularemia was in 1980 in Marivan, southwestern Kurdistan province. A new period of research activities focused on the center began in 2010. The results of researches in this period were further reports of plague, tularemia and Q fever in Iran. After decades of lack of reporting about these diseases, the surveillance system of these diseases formed again. Results of carried out research projects managed by this center includes reports on plague in rodents and dogs in the western part of the country, reports on tularemia seropositivity in human high-risk groups in Kurdistan and Sistan and Baluchestan provinces and the first report of endocarditis case of Q fever in Tehran. In addition, this research center has a close scientific relationship with the national reference laboratory of Arboviruses and viral haemorrhagic fever in Pasteur Institute of Iran to monitor other emerging and reemerging infectious diseases such as Crimean Congo haemorrhagic fever, dengue fever, West Nile fever, Rift Valley fever, etc. To monitor other emerging and reemerging infectious diseases, studies have been done on diseases such as recurrent fever, HIV, tuberculosis and hepatitis. Published articles from the center's experts in the field emerging and reemerging infectious diseases are published in papers in international journals. The center's scientific cooperation is in the form of national and international cooperation: Currently the center has an agreement of collaboration with the Center of Communicable Diseases Control, Hamadan University of Medical Sciences, Rodentology Group of Ferdowsi University of Mashhad, Iranian Association of Microbiology and collaboration with the Tehran University of Medical Sciences and Kurdistan University of Medical Sciences. Scientific development and growth of a new phase of scientific activities were beholden to collaboration with Pasteur Institute of Paris and Pasteur Institute in Madagascar. These two institutes are World Health Organization collaborating centers for plague. The center's educational activities are in the form of workshops, implementation of educational courses and internships and apprenticeship courses, guidance and advice for students' theses and holding journal clubs. A standard program is developed for students to successfully complete different apprenticeship courses in related fields at this center. The following services are performed by the center: Investigation and control of emerging and reemerging infectious disease outbreaks through missions around the country laboratory services for diagnosis of plague, tularemia and Q fever Consultancy to the center for communicable diseases control Following the center for communicable diseases control's request, more than 15 missions around the country has been made to control and investigate different outbreaks during the last 3 years. In December 2014 this center got the certificate to be the National Reference Laboratory for diagnosis of Plague, Tularemia and Q fever. In the repair and rebuilding of the center, a museum was established to house the center's documents and historical devices.Results of carried out research projects managed by this center includes reports on plague in rodents and dogs in the western part of the country, reports on tularemia seropositivity in human high-risk groups in Kurdistan and Sistan and Baluchestan provinces and the first report of endocarditis case of Q fever in Tehran. In addition, this research center has a close scientific relationship with the national reference laboratory of Arboviruses and viral haemorrhagic fever in Pasteur Institute of Iran to monitor other emerging and reemerging infectious diseases such as Crimean Congo haemorrhagic fever, dengue fever, West Nile fever, Rift Valley fever, etc. To monitor other emerging and reemerging infectious diseases, studies have been done on diseases such as recurrent fever, HIV, tuberculosis and hepatitis. Published articles from the center's experts in the field emerging and reemerging infectious diseases are published in papers in international journals. The center's scientific cooperation is in the form of national and international cooperation: Currently the center has an agreement of collaboration with the Center of Communicable Diseases Control, Hamadan University of Medical Sciences, Rodentology Group of Ferdowsi University of Mashhad, Iranian Association of Microbiology and collaboration with the Tehran University of Medical Sciences and Kurdistan University of Medical Sciences. Scientific development and growth of a new phase of scientific activities were beholden to collaboration with Pasteur Institute of Paris and Pasteur Institute in Madagascar. These two institutes are World Health Organization collaborating centers for plague.Results of carried out research projects managed by this center includes reports on plague in rodents and dogs in the western part of the country, reports on tularemia seropositivity in human high-risk groups in Kurdistan and Sistan and Baluchestan provinces and the first report of endocarditis case of Q fever in Tehran. In addition, this research center has a close scientific relationship with the national reference laboratory of Arboviruses and viral haemorrhagic fever in Pasteur Institute of Iran to monitor other emerging and reemerging infectious diseases such as Crimean Congo haemorrhagic fever, dengue fever, West Nile fever, Rift Valley fever, etc. To monitor other emerging and reemerging infectious diseases, studies have been done on diseases such as recurrent fever, HIV, tuberculosis and hepatitis.Published articles from the center's experts in the field emerging and reemerging infectious diseases are published in papers in international journals. The center's scientific cooperation is in the form of national and international cooperation: Currently the center has an agreement of collaboration with the Center of Communicable Diseases Control, Hamadan University of Medical Sciences, Rodentology Group of Ferdowsi University of Mashhad, Iranian Association of Microbiology and collaboration with the Tehran University of Medical Sciences and Kurdistan University of Medical Sciences. Scientific development and growth of a new phase of scientific activities were beholden to collaboration with Pasteur Institute of Paris and Pasteur Institute in Madagascar. These two institutes are World Health Organization collaborating centers for plague.The center's scientific cooperation is in the form of national and international cooperation:Currently the center has an agreement of collaboration with the Center of Communicable Diseases Control, Hamadan University of Medical Sciences, Rodentology Group of Ferdowsi University of Mashhad, Iranian Association of Microbiology and collaboration with the Tehran University of Medical Sciences and Kurdistan University of Medical Sciences.Scientific development and growth of a new phase of scientific activities were beholden to collaboration with Pasteur Institute of Paris and Pasteur Institute in Madagascar. These two institutes are World Health Organization collaborating centers for plague.The center's educational activities are in the form of workshops, implementation of educational courses and internships and apprenticeship courses, guidance and advice for students' theses and holding journal clubs. A standard program is developed for students to successfully complete different apprenticeship courses in related fields at this center.A standard program is developed for students to successfully complete different apprenticeship courses in related fields at this center.The following services are performed by the center: Investigation and control of emerging and reemerging infectious disease outbreaks through missions around the country laboratory services for diagnosis of plague, tularemia and Q fever Consultancy to the center for communicable diseases control Following the center for communicable diseases control's request, more than 15 missions around the country has been made to control and investigate different outbreaks during the last 3 years. In December 2014 this center got the certificate to be the National Reference Laboratory for diagnosis of Plague, Tularemia and Q fever. In the repair and rebuilding of the center, a museum was established to house the center's documents and historical devices.Following the center for communicable diseases control's request, more than 15 missions around the country has been made to control and investigate different outbreaks during the last 3 years.In December 2014 this center got the certificate to be the National Reference Laboratory for diagnosis of Plague, Tularemia and Q fever.In the repair and rebuilding of the center, a museum was established to house the center's documents and historical devices.The Research Center employs 4 faculty members, 13 experts and a caretaker either permanently or temporarily.

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Crimean-Congo haemorrhagic fever

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Colorado tick fever

Colorado tick fever (CTF) is a viral infection ( Coltivirus ) transmitted from the bite of an infected Rocky Mountain wood tick ( Dermacentor andersoni ). It should not be confused with the bacterial tick-borne infection, Rocky Mountain spotted fever . Colorado tick fever is probably the same disease that American pioneers referred to as "mountain fever". Colorado tick fever virus (CTFV) infects haemopoietic cells, particularly erythrocytes , which explains how the virus is transmitted by ticks and also accounts for the incidence of transmission by blood transfusion. [ citation needed ]The first signs and symptoms of Colorado Tick Fever are shown between the 1 and 14th day after the bite from the tick. Once bit by the tick and the onset of symptoms is presented, one will more often then not experience a biphasic fever. A biphasic fever, is a fever that will attack, only to let you feel better, just to infect you once again. Although the virus may only last a couple of weeks, the Virus can be found in the red blood cells for up to 6 months after being cured . Initial symptoms include fever, chills, headaches, pain behind the eyes, light sensitivity, muscle pain, generalized malaise, abdominal pain, hepatosplenomegaly, nausea and vomiting, and a flat or pimply rash. During the second phase of the virus, a high fever can return with an increase in symptoms. CTF can be very severe in cases involving children and can even require hospitalization. Complications with this disease have included aseptic meningitis, encephalitis, and hemorrhagic fever, but these are rare. [ citation needed ] CTF is seasonal, mostly occurring in the Rocky Mountain region of the United States and usually in altitudes from 4,000 to 10,000 feet (1,600 to 3,000 meters). Patients with CTF are mostly campers and young males, who most likely have been bitten because of their activities.The virus particle, like other coltiviruses, is about 80 nm in diameter and is generally not enveloped. The double-stranded RNA viral genome is about 20,000 bp long and is divided into 12 segments, which are termed Seg-1 to Seg-12. Viral replication in infected cells is associated with characteristic cytoplasmic granular matrices. Evidence suggests the viral presence in mature erythrocytes is a result of replication of the virus in hematopoietic erythrocyte precursor cells and simultaneous maturation of the infected immature cells rather than of direct entry and replication of CTFV in mature erythrocytes. The Rocky Mountain wood tick is usually found attached to a host, but when it is without a host, it hides in cracks and crevices, as well as soil. If for some reason the tick is not able to find a host before the winter, it will stay under ground cover until spring, when it can resume its search. The behavior of the Rocky Mountain wood tick varies with its life stages: adults are active as early as March, peaking in April and May, while nymphs and larvae are active around April and June respectively. By late summer or early fall, all these stages typically disappear. Small mammals are common hosts for larvae and nymphs, while adults generally feed on larger mammals such as horses, cattle, and deer. Colorado tick fever (CTF) is transmitted through the bite of an infected Rocky Mountain wood tick . The ticks become carriers of the CTF virus by feeding on infected reservoir animals like small rodents. Transmission from a tick to person is the most common cause of infection. Person-to-person transmission is not typical but can occur rarely through blood transfusions. Post-infection, the CTF virus can linger in red blood cells for several months, hence, blood and bone marrow donations are discouraged for six months following infection. The virus particle, like other coltiviruses, is about 80 nm in diameter and is generally not enveloped. The double-stranded RNA viral genome is about 20,000 bp long and is divided into 12 segments, which are termed Seg-1 to Seg-12. Viral replication in infected cells is associated with characteristic cytoplasmic granular matrices. Evidence suggests the viral presence in mature erythrocytes is a result of replication of the virus in hematopoietic erythrocyte precursor cells and simultaneous maturation of the infected immature cells rather than of direct entry and replication of CTFV in mature erythrocytes. The Rocky Mountain wood tick is usually found attached to a host, but when it is without a host, it hides in cracks and crevices, as well as soil. If for some reason the tick is not able to find a host before the winter, it will stay under ground cover until spring, when it can resume its search. The behavior of the Rocky Mountain wood tick varies with its life stages: adults are active as early as March, peaking in April and May, while nymphs and larvae are active around April and June respectively. By late summer or early fall, all these stages typically disappear. Small mammals are common hosts for larvae and nymphs, while adults generally feed on larger mammals such as horses, cattle, and deer. Colorado tick fever (CTF) is transmitted through the bite of an infected Rocky Mountain wood tick . The ticks become carriers of the CTF virus by feeding on infected reservoir animals like small rodents. Transmission from a tick to person is the most common cause of infection. Person-to-person transmission is not typical but can occur rarely through blood transfusions. Post-infection, the CTF virus can linger in red blood cells for several months, hence, blood and bone marrow donations are discouraged for six months following infection. A combination of clinical signs, symptoms, and laboratory tests can confirm the likelihood of having CTF. Some tests include complement fixation to Colorado tick virus, immunofluorescence for Colorado tick fever, and some other common laboratory findings suggestive of CTF, including leucopenia, thrombocytopenia, and mildly elevated liver enzyme levels. Detection of viral antibodies on red blood cells is possible. To avoid tick bites and infection, experts advise: Avoid tick-infested areas, especially during the warmer months. Wear light-colored clothing so ticks can be easily seen. Wear a long sleeved shirt, hat, long pants, and tuck pant legs into socks. Walk in the center of trails to avoid overhanging grass and brush. Clothing and body parts should be checked every few hours for ticks when spending time outdoors in tick-infested areas. Ticks are most often found on the thigh, arms, underarms, and legs. Ticks can be very small (no bigger than a pinhead). Look carefully for new "freckles". The use of insect repellents containing DEET on skin or permethrin on clothing can be effective. Follow the directions on the container and wash off repellents when going indoors. Remove attached ticks immediately. Contracting the CTF virus is thought to provide long-lasting immunity against reinfection. However, it is always wise to be on the safe side and try to prevent tick bites. No specific treatment for CTF is yet available. The first action is to make sure the tick is fully removed from the skin, then acetaminophen and analgesics can be used to help relieve the fever and pain. Aspirin is not recommended for children, as it has been linked to Reye's syndrome in some viral illnesses. Salicylates should not be used because of thrombocytopenia , and the rare occurrence of bleeding disorders. People who suspect they have been bitten by a tick or are starting to show signs of CTF should contact their physicians immediately. Ticks should be removed promptly and carefully with tweezers and by applying gentle, steady traction. The tick's body should not be crushed when it is removed and the tweezers should be placed as close to the skin as possible to avoid leaving tick mouthparts in the skin. Mouthparts left in the skin can allow secondary infections. Ticks should not be removed with bare hands. Hands should be protected by gloves or tissues and thoroughly washed with soap and water after the removal process. A match or flame should not be used to remove a tick. This method, once thought safe, can cause the tick to regurgitate expelling any disease it may be carrying into the bite wound. Ticks should be removed promptly and carefully with tweezers and by applying gentle, steady traction. The tick's body should not be crushed when it is removed and the tweezers should be placed as close to the skin as possible to avoid leaving tick mouthparts in the skin. Mouthparts left in the skin can allow secondary infections. Ticks should not be removed with bare hands. Hands should be protected by gloves or tissues and thoroughly washed with soap and water after the removal process. A match or flame should not be used to remove a tick. This method, once thought safe, can cause the tick to regurgitate expelling any disease it may be carrying into the bite wound. The disease develops from March to September, with the highest infections occurring in June. The disease is found almost exclusively in the western United States and Canada, mostly in high mountain areas such as Colorado and Idaho. The CTFV was first isolated from human blood in 1944.

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Crimean-Congo haemorrhagic fever

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West Nile fever

West Nile fever is an infection by the West Nile virus , which is typically spread by mosquitoes . In about 80% of infections people have few or no symptoms . About 20% of people develop a fever , headache, vomiting, or a rash. In less than 1% of people, encephalitis or meningitis occurs, with associated neck stiffness, confusion, or seizures. Recovery may take weeks to months. The risk of death among those in whom the nervous system is affected is about 10 percent. West Nile virus (WNV) is usually spread by mosquitoes that become infected when they feed on infected birds, which often carry the disease . Rarely the virus is spread through blood transfusions, organ transplants, or from mother to baby during pregnancy, delivery, or breastfeeding, but it otherwise does not spread directly between people. Risks for severe disease include being over 60 years old and having other health problems. Diagnosis is typically based on symptoms and blood tests. There is no human vaccine . The best way to reduce the risk of infection is to avoid mosquito bites. Mosquito populations may be reduced by eliminating standing pools of water, such as in old tires, buckets, gutters, and swimming pools. When mosquitoes cannot be avoided, mosquito repellent , window screens , and mosquito nets reduce the likelihood of being bitten. There is no specific treatment for the disease; pain medications may reduce symptoms. The virus was discovered in Uganda in 1937, and was first detected in North America in 1999. WNV has occurred in Europe, Africa, Asia, Australia, and North America. In the United States thousands of cases are reported a year, with most occurring in August and September. It can occur in outbreaks of disease. Severe disease may also occur in horses, for which a vaccine is available. A surveillance system in birds is useful for early detection of a potential human outbreak. About 80% of those infected with West Nile virus (WNV) show no symptoms and go unreported. About 20% of infected people develop symptoms. These vary in severity, and begin 3 to 14 days after being bitten. Most people with mild symptoms of WNV recover completely, though fatigue and weakness may last for weeks or months. Symptoms may range from mild, such as fever , to severe, such as paralysis and meningitis . A severe infection can last weeks and can, rarely, cause permanent brain damage . Death may ensue if the central nervous system is affected. Medical conditions such as cancer and diabetes , and age over 60 years, increase the risk of developing severe symptoms. Headache can be a prominent symptom of WNV fever, meningitis, encephalitis, meningoencephalitis, and it may or may not be present in poliomyelitis-like syndrome. Thus, headache is not a useful indicator of neuroinvasive disease.WNV is one of the Japanese encephalitis antigenic serocomplex of viruses. Image reconstructions and cryoelectron microscopy reveal a 45–50 nm virion covered with a relatively smooth protein surface. This structure is similar to the dengue fever virus; both belong to the genus Flavivirus within the family Flaviviridae . The genetic material of WNV is a positive-sense , single strand of RNA , which is between 11,000 and 12,000 nucleotides long; these genes encode seven nonstructural proteins and three structural proteins. The RNA strand is held within a nucleocapsid formed from 12- kDa protein blocks; the capsid is contained within a host-derived membrane altered by two viral membrane proteins. West Nile virus has been seen to replicate faster and spread more easily to birds at higher temperatures; one of several ways climate change could affect the epidemiology of this disease. The prime method of spread of the West Nile virus (WNV) is the female mosquito. In Europe, cats were identified as being hosts for West Nile virus . The important mosquito vectors vary according to area; in the United States, Culex pipiens (Eastern United States, and urban and residential areas of the United States north of 36–39°N), Culex tarsalis (Midwest and West), and Culex quinquefasciatus (Southeast) are the main vector species. The mosquito species that are most frequently infected with WNV feed primarily on birds. Different species of mosquitos take a blood meal from different types of vertebrate hosts , Mosquitoes show further selectivity, exhibiting preference for different species of birds. In the United States, WNV mosquito vectors feed preferentially on members of the Corvidae and thrush family . Among the preferred species within these families are the American crow , a corvid, and the American robin ( Turdus migratorius ). Some species of birds develop sufficient viral levels (>~10 4.2 log PFU/ml; ) after being infected to transmit the infection to biting mosquitoes that in turn go on to infect other birds. In birds that die from WNV, death usually occurs after 4 to 6 days. In mammals and several species of birds, the virus does not multiply as readily and so does not develop high viremia during infection. Mosquitoes biting such hosts are not believed to ingest sufficient virus to become infected, making them so-called dead-end hosts . As a result of the differential infectiousness of hosts, the feeding patterns of mosquitoes play an important role in WNV transmission, and they are partly genetically controlled, even within a species. Direct human-to-human transmission initially was believed to be caused only by occupational exposure, such as in a laboratory setting, or conjunctival exposure to infected blood. The US outbreak identified additional transmission methods through blood transfusion, organ transplant, intrauterine exposure, and breast feeding. Since 2003, blood banks in the United States routinely screen for the virus among their donors. As a precautionary measure, the UK's National Blood Service initially ran a test for this disease in donors who donate within 28 days of a visit to the United States, Canada, or the northeastern provinces of Italy, and the Scottish National Blood Transfusion Service asks prospective donors to wait 28 days after returning from North America or the northeastern provinces of Italy before donating. There also have been reports of possible transmission of the virus from mother to child during pregnancy or breastfeeding or exposure to the virus in a lab, but these are rare cases and not conclusively confirmed. Recently, the potential for mosquito saliva to affect the course of WNV disease was demonstrated. Mosquitoes inoculate their saliva into the skin while obtaining blood. Mosquito saliva is a pharmacological cocktail of secreted molecules, principally proteins, that can affect vascular constriction, blood coagulation , platelet aggregation , inflammation , and immunity . It clearly alters the immune response in a manner that may be advantageous to a virus. Studies have shown it can specifically modulate the immune response during early virus infection, and mosquito feeding can exacerbate WNV infection, leading to higher viremia and more severe forms of disease. Vertical transmission , the transmission of a viral or bacterial disease from the female of the species to her offspring, has been observed in various West Nile virus studies, amongst different species of mosquitoes in both the laboratory and in nature. Mosquito progeny infected vertically in autumn may potentially serve as a mechanism for WNV to overwinter and initiate enzootic horizontal transmission the following spring, although it likely plays little role in transmission in the summer and fall. Risk factors independently associated with developing a clinical infection with WNV include a suppressed immune system and a patient history of organ transplantation. For neuroinvasive disease the additional risk factors include older age (>50+), male sex, hypertension , and diabetes mellitus . A genetic factor also appears to increase susceptibility to West Nile disease. A mutation of the gene CCR5 gives some protection against HIV but leads to more serious complications of WNV infection. Carriers of two mutated copies of CCR5 made up 4.0 to 4.5% of a sample of people with West Nile disease, while the incidence of the gene in the general population is only 1.0%. The most at risk occupations in the U.S. are outdoor workers, for example farmers, loggers, landscapers/groundskeepers, construction workers, painters, summer camp workers and pavers. Two reports of accidental exposure by laboratory personnel working with infected fluids or tissues have been received. While this appears to be a rare occurrence, it highlights the need for proper handling of infected materials. The World Health Organization states that there are no known cases of health care workers acquiring the virus from infected patients when the appropriate infection control precautions are observed. WNV is one of the Japanese encephalitis antigenic serocomplex of viruses. Image reconstructions and cryoelectron microscopy reveal a 45–50 nm virion covered with a relatively smooth protein surface. This structure is similar to the dengue fever virus; both belong to the genus Flavivirus within the family Flaviviridae . The genetic material of WNV is a positive-sense , single strand of RNA , which is between 11,000 and 12,000 nucleotides long; these genes encode seven nonstructural proteins and three structural proteins. The RNA strand is held within a nucleocapsid formed from 12- kDa protein blocks; the capsid is contained within a host-derived membrane altered by two viral membrane proteins. West Nile virus has been seen to replicate faster and spread more easily to birds at higher temperatures; one of several ways climate change could affect the epidemiology of this disease. The prime method of spread of the West Nile virus (WNV) is the female mosquito. In Europe, cats were identified as being hosts for West Nile virus . The important mosquito vectors vary according to area; in the United States, Culex pipiens (Eastern United States, and urban and residential areas of the United States north of 36–39°N), Culex tarsalis (Midwest and West), and Culex quinquefasciatus (Southeast) are the main vector species. The mosquito species that are most frequently infected with WNV feed primarily on birds. Different species of mosquitos take a blood meal from different types of vertebrate hosts , Mosquitoes show further selectivity, exhibiting preference for different species of birds. In the United States, WNV mosquito vectors feed preferentially on members of the Corvidae and thrush family . Among the preferred species within these families are the American crow , a corvid, and the American robin ( Turdus migratorius ). Some species of birds develop sufficient viral levels (>~10 4.2 log PFU/ml; ) after being infected to transmit the infection to biting mosquitoes that in turn go on to infect other birds. In birds that die from WNV, death usually occurs after 4 to 6 days. In mammals and several species of birds, the virus does not multiply as readily and so does not develop high viremia during infection. Mosquitoes biting such hosts are not believed to ingest sufficient virus to become infected, making them so-called dead-end hosts . As a result of the differential infectiousness of hosts, the feeding patterns of mosquitoes play an important role in WNV transmission, and they are partly genetically controlled, even within a species. Direct human-to-human transmission initially was believed to be caused only by occupational exposure, such as in a laboratory setting, or conjunctival exposure to infected blood. The US outbreak identified additional transmission methods through blood transfusion, organ transplant, intrauterine exposure, and breast feeding. Since 2003, blood banks in the United States routinely screen for the virus among their donors. As a precautionary measure, the UK's National Blood Service initially ran a test for this disease in donors who donate within 28 days of a visit to the United States, Canada, or the northeastern provinces of Italy, and the Scottish National Blood Transfusion Service asks prospective donors to wait 28 days after returning from North America or the northeastern provinces of Italy before donating. There also have been reports of possible transmission of the virus from mother to child during pregnancy or breastfeeding or exposure to the virus in a lab, but these are rare cases and not conclusively confirmed. Recently, the potential for mosquito saliva to affect the course of WNV disease was demonstrated. Mosquitoes inoculate their saliva into the skin while obtaining blood. Mosquito saliva is a pharmacological cocktail of secreted molecules, principally proteins, that can affect vascular constriction, blood coagulation , platelet aggregation , inflammation , and immunity . It clearly alters the immune response in a manner that may be advantageous to a virus. Studies have shown it can specifically modulate the immune response during early virus infection, and mosquito feeding can exacerbate WNV infection, leading to higher viremia and more severe forms of disease. Vertical transmission , the transmission of a viral or bacterial disease from the female of the species to her offspring, has been observed in various West Nile virus studies, amongst different species of mosquitoes in both the laboratory and in nature. Mosquito progeny infected vertically in autumn may potentially serve as a mechanism for WNV to overwinter and initiate enzootic horizontal transmission the following spring, although it likely plays little role in transmission in the summer and fall. Vertical transmission , the transmission of a viral or bacterial disease from the female of the species to her offspring, has been observed in various West Nile virus studies, amongst different species of mosquitoes in both the laboratory and in nature. Mosquito progeny infected vertically in autumn may potentially serve as a mechanism for WNV to overwinter and initiate enzootic horizontal transmission the following spring, although it likely plays little role in transmission in the summer and fall. Risk factors independently associated with developing a clinical infection with WNV include a suppressed immune system and a patient history of organ transplantation. For neuroinvasive disease the additional risk factors include older age (>50+), male sex, hypertension , and diabetes mellitus . A genetic factor also appears to increase susceptibility to West Nile disease. A mutation of the gene CCR5 gives some protection against HIV but leads to more serious complications of WNV infection. Carriers of two mutated copies of CCR5 made up 4.0 to 4.5% of a sample of people with West Nile disease, while the incidence of the gene in the general population is only 1.0%. The most at risk occupations in the U.S. are outdoor workers, for example farmers, loggers, landscapers/groundskeepers, construction workers, painters, summer camp workers and pavers. Two reports of accidental exposure by laboratory personnel working with infected fluids or tissues have been received. While this appears to be a rare occurrence, it highlights the need for proper handling of infected materials. The World Health Organization states that there are no known cases of health care workers acquiring the virus from infected patients when the appropriate infection control precautions are observed. Preliminary diagnosis is often based on the patient's clinical symptoms, places and dates of travel (if patient is from a non endemic country or area), activities, and epidemiologic history of the location where infection occurred. A recent history of mosquito bites and an acute febrile illness associated with neurologic signs and symptoms should cause clinical suspicion of WNV. Diagnosis of West Nile virus infections is generally accomplished by serologic testing of blood serum or cerebrospinal fluid (CSF), which is obtained via a lumbar puncture . Initial screening could be done using the ELISA technique detecting immunoglobulins in the sera of the tested individuals. Typical findings of WNV infection include lymphocytic pleocytosis , elevated protein level, reference glucose and lactic acid levels, and no erythrocytes . Definitive diagnosis of WNV is obtained through detection of virus-specific antibody IgM and neutralizing antibodies . Cases of West Nile virus meningitis and encephalitis that have been serologically confirmed produce similar degrees of CSF pleocytosis and are often associated with substantial CSF neutrophilia . Specimens collected within eight days following onset of illness may not test positive for West Nile IgM, and testing should be repeated. A positive test for West Nile IgG in the absence of a positive West Nile IgM is indicative of a previous flavivirus infection and is not by itself evidence of an acute West Nile virus infection. If cases of suspected West Nile virus infection, sera should be collected on both the acute and convalescent phases of the illness. Convalescent specimens should be collected 2–3 weeks after acute specimens. It is common in serologic testing for cross-reactions to occur among flaviviruses such as dengue virus (DENV) and tick-borne encephalitis virus ; this necessitates caution when evaluating serologic results of flaviviral infections. Four FDA -cleared WNV IgM ELISA kits are commercially available from different manufacturers in the U.S., each of these kits is indicated for use on serum to aid in the presumptive laboratory diagnosis of WNV infection in patients with clinical symptoms of meningitis or encephalitis. Positive WNV test results obtained via use of these kits should be confirmed by additional testing at a state health department laboratory or CDC. In fatal cases, nucleic acid amplification, histopathology with immunohistochemistry , and virus culture of autopsy tissues can also be useful. Only a few state laboratories or other specialized laboratories, including those at CDC, are capable of doing this specialized testing. A number of various diseases may present with symptoms similar to those caused by a clinical West Nile virus infection. Those causing neuroinvasive disease symptoms include the enterovirus infection and bacterial meningitis. Accounting for differential diagnoses is a crucial step in the definitive diagnosis of WNV infection. Consideration of a differential diagnosis is required when a patient presents with unexplained febrile illness, extreme headache, encephalitis or meningitis. Diagnostic and serologic laboratory testing using polymerase chain reaction (PCR) testing and viral culture of CSF to identify the specific pathogen causing the symptoms, is the only currently available means of differentiating between causes of encephalitis and meningitis. A number of various diseases may present with symptoms similar to those caused by a clinical West Nile virus infection. Those causing neuroinvasive disease symptoms include the enterovirus infection and bacterial meningitis. Accounting for differential diagnoses is a crucial step in the definitive diagnosis of WNV infection. Consideration of a differential diagnosis is required when a patient presents with unexplained febrile illness, extreme headache, encephalitis or meningitis. Diagnostic and serologic laboratory testing using polymerase chain reaction (PCR) testing and viral culture of CSF to identify the specific pathogen causing the symptoms, is the only currently available means of differentiating between causes of encephalitis and meningitis. Many of the guidelines for preventing occupational West Nile virus exposure are common to all mosquito-borne diseases . Public health measures include taking steps to reduce mosquito populations. Personal recommendations are to reduce the likelihood of being bitten. General measures to avoid bites include: West Nile virus can be sampled from the environment by the pooling of trapped mosquitoes via ovitraps , carbon dioxide -baited light traps, and gravid traps, testing blood samples drawn from wild birds, dogs, and sentinel monkeys, and testing brains of dead birds found by various animal control agencies and the public. [ citation needed ] Testing of the mosquito samples requires the use of reverse-transcriptase PCR ( RT-PCR ) to directly amplify and show the presence of virus in the submitted samples. When using the blood sera of wild birds and sentinel chickens, samples must be tested for the presence of WNV antibodies by use of immunohistochemistry (IHC) or enzyme-linked immunosorbent assay (ELISA). Dead birds, after necropsy , or their oral swab samples collected on specific RNA-preserving filter paper card, can have their virus presence tested by either RT-PCR or IHC, where virus shows up as brown-stained tissue because of a substrate- enzyme reaction. West Nile control is achieved through mosquito control , by elimination of mosquito breeding sites such as abandoned pools, applying larvacide to active breeding areas, and targeting the adult population via lethal ovitraps and aerial spraying of pesticides . [ citation needed ] Environmentalists have condemned attempts to control the transmitting mosquitoes by spraying pesticide, saying the detrimental health effects of spraying outweigh the relatively few lives that may be saved, and more environmentally friendly ways of controlling mosquitoes are available. They also question the effectiveness of insecticide spraying, as they believe mosquitoes that are resting or flying above the level of spraying will not be killed; the most common vector in the northeastern United States, Culex pipiens , is a canopy feeder. [ citation needed ]West Nile virus can be sampled from the environment by the pooling of trapped mosquitoes via ovitraps , carbon dioxide -baited light traps, and gravid traps, testing blood samples drawn from wild birds, dogs, and sentinel monkeys, and testing brains of dead birds found by various animal control agencies and the public. [ citation needed ] Testing of the mosquito samples requires the use of reverse-transcriptase PCR ( RT-PCR ) to directly amplify and show the presence of virus in the submitted samples. When using the blood sera of wild birds and sentinel chickens, samples must be tested for the presence of WNV antibodies by use of immunohistochemistry (IHC) or enzyme-linked immunosorbent assay (ELISA). Dead birds, after necropsy , or their oral swab samples collected on specific RNA-preserving filter paper card, can have their virus presence tested by either RT-PCR or IHC, where virus shows up as brown-stained tissue because of a substrate- enzyme reaction. West Nile control is achieved through mosquito control , by elimination of mosquito breeding sites such as abandoned pools, applying larvacide to active breeding areas, and targeting the adult population via lethal ovitraps and aerial spraying of pesticides . [ citation needed ] Environmentalists have condemned attempts to control the transmitting mosquitoes by spraying pesticide, saying the detrimental health effects of spraying outweigh the relatively few lives that may be saved, and more environmentally friendly ways of controlling mosquitoes are available. They also question the effectiveness of insecticide spraying, as they believe mosquitoes that are resting or flying above the level of spraying will not be killed; the most common vector in the northeastern United States, Culex pipiens , is a canopy feeder. [ citation needed ]No specific treatment is available for WNV infection. Most people recover without treatment. In mild cases, over-the-counter pain relievers can help ease mild headaches and muscle aches in adults. In severe cases supportive care is provided, often in hospital, with intravenous fluids , pain medication, respiratory support, and prevention of secondary infections. While the general prognosis is favorable, current studies indicate that West Nile Fever can often be more severe than previously recognized, with studies of various recent outbreaks indicating that it may take as long as 60 to 90 days to recover. Patients with milder WNF are just as likely as those with more severe manifestations of neuroinvasive disease to experience multiple somatic complaints such as tremor, and dysfunction in motor skills and executive functions for over a year. People with milder symptoms are just as likely as people with more severe symptoms to experience adverse outcomes. Recovery is marked by a long convalescence with fatigue . One study found that neuroinvasive WNV infection was associated with an increased risk for subsequent kidney disease. WNV was first isolated from a feverish 37-year-old woman at Omogo in the West Nile District of Uganda in 1937 during research on yellow fever virus . A series of serosurveys in 1939 in central Africa found anti-WNV positive results ranging from 1.4% (Congo) to 46.4% (White Nile region, Sudan). It was subsequently identified in Egypt (1942) and India (1953), a 1950 serosurvey in Egypt found 90% of those over 40 years in age had WNV antibodies. The ecology was characterized in 1953 with studies in Egypt and Israel . The virus became recognized as a cause of severe human meningoencephalitis in elderly patients during an outbreak in Israel in 1957. The disease was first noted in horses in Egypt and France in the early 1960s and found to be widespread in southern Europe, southwest Asia and Australia. [ citation needed ] The first appearance of WNV in the Western Hemisphere was in 1999 with encephalitis reported in humans, dogs, cats, and horses, and the subsequent spread in the United States may be an important milestone in the evolving history of this virus. The American outbreak began in College Point, Queens in New York City and was later spread to the neighboring states of New Jersey and Connecticut . The virus is believed to have entered in an infected bird or mosquito, although there is no clear evidence. West Nile virus is now endemic in Africa, Europe, the Middle East, west and central Asia, Oceania (subtype Kunjin ), and most recently, North America and is spreading into Central and South America. Outbreaks of West Nile virus encephalitis in humans have occurred in Algeria (1994), Romania (1996 to 1997), the Czech Republic (1997), Congo (1998), Russia (1999), the United States (1999 to 2009), Canada (1999–2007), Israel (2000) and Greece (2010). Epizootics of disease in horses occurred in Morocco (1996), Italy (1998), the United States (1999 to 2001), and France (2000), Mexico (2003) and Sardinia (2011). [ citation needed ] Outdoor workers (including biological fieldworkers, construction workers, farmers, landscapers, and painters), healthcare personnel, and laboratory personnel who perform necropsies on animals are at risk of contracting WNV. In 2012, the US experienced one of its worst epidemics in which 286 people died, with the state of Texas being hard hit by this virus. Drought has been associated with a higher number of West Nile virus cases in the following year. As drought can decrease fish and other populations that eat mosquito eggs, higher numbers of mosquitoes can result. Higher temperatures are linked to decreased time for replication and increased viral load in birds and mosquitoes. Drought has been associated with a higher number of West Nile virus cases in the following year. As drought can decrease fish and other populations that eat mosquito eggs, higher numbers of mosquitoes can result. Higher temperatures are linked to decreased time for replication and increased viral load in birds and mosquitoes. A vaccine for horses ( ATCvet code: QI05AA10 ( WHO ) ) based on killed viruses exists; some zoos have given this vaccine to their birds, although its effectiveness is unknown. Dogs and cats show few if any signs of infection. There have been no known cases of direct canine-human or feline-human transmission; although these pets can become infected, it is unlikely they are, in turn, capable of infecting native mosquitoes and thus continuing the disease cycle. AMD3100 , which had been proposed as an antiretroviral drug for HIV, has shown promise against West Nile encephalitis. Morpholino antisense oligos conjugated to cell penetrating peptides have been shown to partially protect mice from WNV disease. There have also been attempts to treat infections using ribavirin , intravenous immunoglobulin , or alpha interferon . GenoMed, a U.S. biotech company, has found that blocking angiotensin II can treat the " cytokine storm " of West Nile virus encephalitis as well as other viruses. As of 2019, six vaccines had progressed to human trials but none had been licensed in the United States. Only the two live attenuated vaccines produced strong immunity after a single dose.

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Crimean-Congo haemorrhagic fever

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Arenavirus

An arenavirus is a bi- or trisegmented ambisense RNA virus that is a member of the family Arenaviridae . These viruses infect rodents and occasionally humans. A class of novel, highly divergent arenaviruses, properly known as reptarenaviruses, have also been discovered which infect snakes to produce inclusion body disease , mostly in boa constrictors . At least eight arenaviruses are known to cause human disease. The diseases derived from arenaviruses range in severity. Aseptic meningitis, a severe human disease that causes inflammation covering the brain and spinal cord, can arise from the lymphocytic choriomeningitis virus . Hemorrhagic fever syndromes, including Lassa fever , are derived from infections such as Guanarito virus , Junin virus , Lassa virus , Lujo virus , Machupo virus , Sabia virus , or Whitewater Arroyo virus . Because of the epidemiological association with rodents, some arenaviruses and bunyaviruses are designated as roboviruses .Viewed in cross-section, arenaviruses contain grainy particles that are ribosomes acquired from their host cells. It is from this characteristic that they acquired the name arena , from the Latin root meaning sand . The ribosomal structures are not believed to be essential for virus replication. Virus particles, or virions, are pleomorphic (variable in shape) but are often spherical, with a diameter of 60–300 nm, and are covered with surface glycoprotein spikes. The virus contains a beaded nucleocapsid with two single-stranded RNA segments. The nucleocapsid consists of a core of nucleic acid enclosed in a protein coat. Although they are categorized as negative-sense viruses, arenaviruses are ambisense . While sections of their genome encode genes in the negative sense (reverse polarity), other sections encode genes in the opposite (forward/positive sense) direction. This complex gene expression structure is theorized to be a primitive regulatory system, allowing the virus to control what proteins are synthesized at what point in the life cycle. The life cycle of the arenavirus is restricted to the cell cytoplasm. [ citation needed ]Arenaviruses have a segmented RNA genome that consists of two single-stranded ambisense RNAs. As with all negative-sense RNA viruses, the genomic RNA alone is not infectious and the viral replication machinery is required to initiate infection within a host cell. Genomic sense RNA packaged into the arenavirus virion is designated negative-sense RNA, and must first be copied into a positive-sense mRNA in order to produce viral protein . The RNA segments are denoted Small (S), Medium (M; if present), and Large (L), and code for four viral proteins in a unique ambisense coding strategy. For mammarenaviruses and reptarenaviruses, each RNA segment codes for two viral proteins in opposite orientation such that the negative-sense RNA genome serves as the template for transcription of a single mRNA and the positive-sense copy of the RNA genome templates a second mRNA . The separate coding sequences of the two viral proteins are divided by an intergenic region RNA sequence that is predicted to fold into a stable hairpin structure. The extreme termini of each RNA segment contains a 19 nucleotide highly conserved sequence that is critical for recruitment of the viral replication machinery and initiation of viral mRNA transcription and genomic replication . The conserved 5' and 3' RNA termini sequences are complementary and allows each RNA segment to adopt a double-stranded RNA panhandle structure that maintains the termini in close proximity and results in a circular appearance to purified arenavirus genomic templates visualized by electron microscopy . The double-stranded RNA panhandle structure is critical for efficient viral RNA synthesis, but potential interterminal double-stranded RNA interactions must be transiently relieved in order to recruit the viral polymerase . The S-segment RNA is approximately 3.5 kb, and encodes the viral nucleocapsid protein (NP) and glycoprotein (GPC). The L-segment RNA is approximately 7.2 kb, and encodes the viral RNA-dependent RNA-polymerase (L) and a small RING-domain containing protein (Z). The Z protein forms homo oligomers and a structural component of the virions. The formation of these oligomers is an essential step for particle assembly and budding. Binding between Z and the viral envelope glycoprotein complex is required for virion infectivity. Z also interacts with the L and NP proteins. Polymerase activity appears to be modulated by the association between the L and Z proteins. Interaction between the Z and NP proteins is critical for genome packaging. [ citation needed ]The glycoprotein (GP) is synthesised as a precursor molecule. It is cleaved into three parts - GP1, GP2 and a stable signal peptide (SSP). These reactions are catalysed by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P). These processes are essential for fusion competence and incorporation of mature GP into nascent budding virion particles. [ citation needed ]Within the family Arenaviridae , arenaviruses were formerly all placed in the genus Arenavirus , but in 2015 were divided into the genera Mammarenavirus for those with mammalian hosts and Reptarenavirus for those infecting snakes. Reptarenaviruses and mammarenavirus are separated by an impenetrable species barrier. Infected rodents cannot pass disease onto snakes, and IBD in captive snakes is not transmissible to humans. [ citation needed ] A third genus, Hartmanivirus (not to be confused with genus Haartmanvirus of vibrio phages in family Demerecviridae , order Caudovirales ), has also been established, including other species that infect snakes. The organisation of the genome of this genus is typical of arenaviruses but their glycoproteins resemble those of filoviruses . Species in this genus lack the matrix protein. A fourth genus, Antennavirus , has also been established to accommodate two arenaviruses found in striated frogfish ( Antennarius striatus ). A third antennavirus has been detected in Chinook salmon and sockeye salmon . Mammarenaviruses can be divided into two serogroups, which differ genetically and by geographical distribution: When the virus is classified "Old World" this means it was found in the Eastern Hemisphere in places such as Europe, Asia, and Africa. When it is found in the Western Hemisphere, in places such as Argentina, Bolivia, Venezuela, Brazil, and the United States, it is classified "New World". Lymphocytic choriomeningitis (LCM) virus is the only mammarenavirus found worldwide because of its ubiquitous Old World host, the house mouse . Old and New World area viruses appear to have diverged ~45,000 years ago. The Old World Mammarenaviruses originated ~23.1-1.88 thousand years ago, most likely in Southern Africa, while the New World Mammarenaviruses evolved in the Latin America-Caribbean region ~41.4-3.3 thousand years ago. The evolution of the Mammarenavirus genus has been studied. The New World and Old World species diverged less than 45,000 years ago. The New World species evolved between 41,400 and 3,300 years ago in the Latin America-Caribbean region. The Old World species evolved between 23,100 and 1,880 years ago, most likely in southern Africa. Some arenaviruses are zoonotic pathogens and are generally associated with rodent —transmitted disease in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. Arenaviruses persist in nature by infecting rodents first and then transmitted into humans. Humans can be infected through mucosal exposure to aerosols, or by direct contact of abraded skin with the infectious material, derived from infected rodents. Aerosols are fine mists or sprays of rodent dried excreta, especially urine that is dropped in the environment. Most of the Arenaviruses caught by humans are within their own homes when these rodents seek shelter. The virus can be caught in factories, from food that has been contaminated, or within agricultural work areas. Humans' risk of contracting the Arenavirus infection is related to age, race, or sex within the degree of contact with the dried rodent excreta. [ citation needed ]Lymphocytic choriomeningitis (LCM) viruses cause influenza-like febrile illness , but occasionally they may cause meningitis, characteristically accompanied by large numbers of lymphocytes in the cerebrospinal fluid (as the name LCM suggests). Lassa virus causes Lassa fever . Lassa fever is endemic in west Africa. The virus was first isolated from Americans stationed in the village of Lassa, Nigeria. The virus can be transmitted person-to-person. Subclinical diseases: Serological studies suggest that inapparent infections particularly among members of hunting tribes are common. Clinical infections: Lassa fever is characterised by high fever, severe myalgia, coagulopathy, haemorrhagic skin rash, and occasional visceral haemorrhage as well as necrosis of liver and spleen. Other Arenaviruses like Junin virus, Machupo virus cause haemorrhagic fevers. Subclinical diseases: Serological studies suggest that inapparent infections particularly among members of hunting tribes are common. Clinical infections: Lassa fever is characterised by high fever, severe myalgia, coagulopathy, haemorrhagic skin rash, and occasional visceral haemorrhage as well as necrosis of liver and spleen. All of these diseases pose a great threat to public health in the regions where it is taking place. For example, when the Old World Lassa virus turns into Lassa fever, this usually results in a significant amount of mortality. Similarly the New World Junin virus causes Argentine hemorrhagic fever. This fever is a severe illness with hemorrhagic and neurological manifestations and a case fatality of fifteen to thirty percent. The way this virus spreads is through increased traveling to and from endemic regions. This traveling has led to the importation of Lassa fever into non-endemic metropolitan areas all over the world. A new species of arenavirus named the Lujo virus has been linked to five patients who exhibited symptoms of viral hemorrhagic fever in South Africa. The disease originated near Lusaka, Zambia and spread to Johannesburg , South Africa , after the first patient was transported to a hospital there. The results of genetic sequencing tests conducted by epidemiologists at Columbia University in New York City , USA, and at the Special Pathogens Branch of the Centers for Disease Control in Atlanta , USA, provided evidence that the causative agent of the disease is a virus from the family Arenaviridae, which ultimately resulted in the deaths of four out of the five infected in Zambia and South Africa during the outbreak which began in September 2008. [ citation needed ] Arenavirus has also pinpointed as the cause of death of three donor organ recipients in Australia who contracted the virus after receiving kidney and a liver donations from a single infected organ donor in late 2006. All three died in the first week of 2007. WHO and its Global Outbreak Alert and Response Network (GOARN) partners continue to support the Ministries of Health of the two countries in various facets of the outbreak investigation, including laboratory diagnosis, investigations, active case finding and follow-up of contacts. Lymphocytic choriomeningitis (LCM) viruses cause influenza-like febrile illness , but occasionally they may cause meningitis, characteristically accompanied by large numbers of lymphocytes in the cerebrospinal fluid (as the name LCM suggests). Lassa virus causes Lassa fever . Lassa fever is endemic in west Africa. The virus was first isolated from Americans stationed in the village of Lassa, Nigeria. The virus can be transmitted person-to-person. Subclinical diseases: Serological studies suggest that inapparent infections particularly among members of hunting tribes are common. Clinical infections: Lassa fever is characterised by high fever, severe myalgia, coagulopathy, haemorrhagic skin rash, and occasional visceral haemorrhage as well as necrosis of liver and spleen. Other Arenaviruses like Junin virus, Machupo virus cause haemorrhagic fevers. Subclinical diseases: Serological studies suggest that inapparent infections particularly among members of hunting tribes are common. Clinical infections: Lassa fever is characterised by high fever, severe myalgia, coagulopathy, haemorrhagic skin rash, and occasional visceral haemorrhage as well as necrosis of liver and spleen. All of these diseases pose a great threat to public health in the regions where it is taking place. For example, when the Old World Lassa virus turns into Lassa fever, this usually results in a significant amount of mortality. Similarly the New World Junin virus causes Argentine hemorrhagic fever. This fever is a severe illness with hemorrhagic and neurological manifestations and a case fatality of fifteen to thirty percent. The way this virus spreads is through increased traveling to and from endemic regions. This traveling has led to the importation of Lassa fever into non-endemic metropolitan areas all over the world.A new species of arenavirus named the Lujo virus has been linked to five patients who exhibited symptoms of viral hemorrhagic fever in South Africa. The disease originated near Lusaka, Zambia and spread to Johannesburg , South Africa , after the first patient was transported to a hospital there. The results of genetic sequencing tests conducted by epidemiologists at Columbia University in New York City , USA, and at the Special Pathogens Branch of the Centers for Disease Control in Atlanta , USA, provided evidence that the causative agent of the disease is a virus from the family Arenaviridae, which ultimately resulted in the deaths of four out of the five infected in Zambia and South Africa during the outbreak which began in September 2008. [ citation needed ] Arenavirus has also pinpointed as the cause of death of three donor organ recipients in Australia who contracted the virus after receiving kidney and a liver donations from a single infected organ donor in late 2006. All three died in the first week of 2007. WHO and its Global Outbreak Alert and Response Network (GOARN) partners continue to support the Ministries of Health of the two countries in various facets of the outbreak investigation, including laboratory diagnosis, investigations, active case finding and follow-up of contacts. Very few treatment methods are available. The current lack of a licensed vaccine and limited therapeutic options for the arenavirus make it arguably among the most neglected virus groups. The only licensed drug for the treatment of human arenavirus infection is the nucleoside analogue ribavirin . Ribavirin reduces morbidity and mortality in humans infected with certain arenaviruses, such as LASV and JUNV infections, if it is taken in the early stages of the disease. Ribavirin displays mixed success in treating severe arenaviral disease and is associated with significant toxicities. Effective antiviral drugs need to be produced at a low cost, taken orally, and able to withstand tropical climates due to the regions where these infections are occurring. For this reason high throughput screening (HTS) of small molecular libraries could be the answer to finding a better remedy. HTS collects libraries of small synthetic molecules that can be used to identify protein promoting "agonist" molecules or protein inhibiting "antagonist" interactions. With HTS sustainable antiviral drugs can be discovered against possible new human pathogenic viruses. Immunotherapy is another potential approach. Monoclonal antibodies against Junin virus have been tested in animal models. An immunotherapeutic agent active against all tested mammarenaviruses that use the transferrin receptor 1 as their receptor was under investigation in 2020. Effective antiviral drugs need to be produced at a low cost, taken orally, and able to withstand tropical climates due to the regions where these infections are occurring. For this reason high throughput screening (HTS) of small molecular libraries could be the answer to finding a better remedy. HTS collects libraries of small synthetic molecules that can be used to identify protein promoting "agonist" molecules or protein inhibiting "antagonist" interactions. With HTS sustainable antiviral drugs can be discovered against possible new human pathogenic viruses. Immunotherapy is another potential approach. Monoclonal antibodies against Junin virus have been tested in animal models. An immunotherapeutic agent active against all tested mammarenaviruses that use the transferrin receptor 1 as their receptor was under investigation in 2020.

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Crimean-Congo haemorrhagic fever

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Venezuelan hemorrhagic fever

Guanarito virus Venezuelan hemorrhagic fever ( VHF ) is a zoonotic human illness first identified in 1989. The disease is most prevalent in several rural areas of central Venezuela and is caused by Guanarito mammarenavirus ( GTOV ) which belongs to the Arenaviridae family. The short-tailed cane mouse ( Zygodontomys brevicauda ) is the main host for GTOV which is spread mostly by inhalation of aerosolized droplets of saliva, respiratory secretions, urine, or blood from infected rodents. Person-to-person spread is possible, but uncommon.VHF has many similarities to Lassa fever and to the arenavirus hemorrhagic fevers that occur in Argentina and Bolivia. It causes fever and malaise followed by hemorrhagic manifestations and convulsions. Some presentations of the virus are also characterized by vascular damage, bleeding diathesis, fever, and multiple organ involvement. Clinical diagnosis of VHF has proven to be difficult based on the nonspecific symptoms . The disease is fatal in 30% of cases and is endemic to Portuguesa state and Barinas state in Venezuela . Treatment and prevention for the VHF virus are limited and there are currently no licensed vaccines available that can act to prevent the disease. However, once infected, ribavirin , an anti-viral drug given intravenously, is one way to treat VHF.Arenaviruses are enveloped, single-stranded, bisegmented RNA viruses with antisense genomes. Based on their antigenic properties, arenaviruses have been classified into two major groups: the Old World arenaviruses, and the New World arenaviruses. Old World arenaviruses include lymphocytic choriomeningitis virus and Lassa virus . New world arena viruses are further broken down into three clades, A, B, and C. The Guanarito arena virus belongs to clade B and is the cause of VHF. On the biosafety level scale of one to four, with four causing the most risk, the viruses causing hemorrhagic fevers have been assigned a four by the CDC. The short-tailed cane mouse, the main host of GTOV, is native to western Venezuela and resides in large numbers in tall grass, cultivated agricultural fields, human homes, and outbuildings. It is speculated that demographic and ecological changes in the rural areas increased the frequency of contact between humans and infected rodents such that VHF emerged. From September 1989 through December 2006, the State of Portuguesa recorded 618 cases of VHF. Nearly all of the cases were individuals who worked or lived in Guanarito during the time they became infected. The case fatality rate was 23.1%. Because the virus is contracted by aerosol dissemination, concern arose shortly after the first cases emerged in 1989 due to fear of biological warfare . Potential biological terrorism agents were identified and categorized in 1999 by the Centers for Disease Control and Prevention (CDC) as part of the Congressional initiative to further response capabilities to biological weapons. Arenaviruses causing hemorrhagic fevers , along with a genus of virus called filoviruses, were categorized in Category A; these are pathogens with the highest potential impact on public health safety. A notable event in the timeline of this virus' scientific knowledge was the unexplained disappearance of a vial of the virus at the University of Texas Medical Branch Galveston National Laboratory, announced 2013 March 24.

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Crimean-Congo haemorrhagic fever

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Pappataci fever

Pappataci fever (also known as Phlebotomus fever and, somewhat confusingly, sandfly fever and three-day fever ) is a vector-borne febrile arboviral infection caused by three serotypes of Phlebovirus . It occurs in subtropical regions of the Eastern Hemisphere . The name, pappataci fever, comes from the Italian word for sandfly ; it is the union of the words pappa (usually this is used as a generic name for food, but in this case it is a verb meaning "eating") and taci (silent), distinguishing these insects from blood-feeding mosquitoes, which produce a typical noise while flying.A few days after the infective bite, a feeling of lassitude, abdominal distress and chills develop followed by fever of 39 to 40 °C (102 to 104 °F) , severe frontal headaches, muscle and joint aches, flushing of the face and a fast heart rate . After two days the fever begins to subside and the temperature returns to normal. Fatigue, a slow heart rate and low blood pressure may persist from a few days to several weeks but complete recovery is the rule. Three serotypes of Phlebovirus are known as the causative agents: Naples virus , Sicilian virus and Toscana virus . [ citation needed ]Although commercial tests are not readily available, diagnosis can be confirmed by serology-based assays or quantitative PCR by laboratories that have developed assays to perform such identification. [ citation needed ]Prevention of sandfly bites, and control of sandflies and their breeding grounds with insecticides are the principal methods for prevention. Mosquito nets may not be sufficient to prevent sandfly bites. [ citation needed ]There is no specific treatment for the disease. Pain killers and fluid replacement may be useful. Pappataci fever is prevalent in the subtropical zone of the Eastern Hemisphere between 20°N and 45°N, particularly in Southern Europe , North Africa , the Balkans , Eastern Mediterranean , Iraq , Iran , Pakistan , Afghanistan and India . The disease is transmitted by the bites of phlebotomine sandflies of the Genus Phlebotomus , in particular, Phlebotomus papatasi , Phlebotomus perniciosus and Phlebotomus perfiliewi . The sandfly becomes infected when biting an infected human in the period between 48 hours before the onset of fever and 24 hours after the end of the fever, and remains infected for its lifetime. Besides this horizontal virus transmission from man to sandfly, the virus can be transmitted in insects transovarially , from an infected female sandfly to its offspring. Pappataci fever is seldom recognised in endemic populations because it is mixed with other febrile illnesses of childhood, but it is more well known among immigrants and military personnel from non-endemic regions.

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Crimean-Congo haemorrhagic fever

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Cache Valley orthobunyavirus

Cache Valley virus Cache Valley orthobunyavirus (CVV) is a member of the order Bunyavirales , genus Orthobunyavirus , and serogroup Bunyamwera, which was first isolated in 1956 from Culiseta inornata mosquitos collected in Utah's Cache Valley . CVV is an enveloped arbovirus , nominally 80–120 nm in diameter, whose genome is composed of three single-stranded, negative-sense RNA segments. The large segment of related bunyaviruses is approximately 6800 bases in length and encodes a probable viral polymerase. The middle CVV segment has a 4463-nucleotide sequence and the smallest segment encodes for the nucleocapsid, and a second non-structural protein. CVV has been known to cause outbreaks of spontaneous abortion and congenital malformations in ruminants such as sheep and cattle . CVV rarely infects humans, but when they are infected it has caused encephalitis and multiorgan failure . The Cache Valley virus genome is split into three parts. The three parts are called the small, medium, and large segments, based on the number of bases. The large segment encodes the L protein, which is the RNA dependent RNA polymerase. The small segment utilizes an open reading frame with alternative initiation sites to encode two proteins. Depending on the initiation site, it can either code for the protein that makes up the nucleocapsid , N, or a non-structural protein , NSs. The medium segment encodes 2 type 1 integral transmembrane glycoproteins, Gn and Gc, as well as a non-structural protein Nsm. The Gc and Gn proteins start as one precursor protein and are then cleaved cotranslationally. They are modified by N-linked glycosylation. The attachment, entry, replication, and release of CVV specifically have not been studied. However, there is information of the replication cycle for the genus orthobunyavirus, which CVV is a part of. A heterodimer of integral transmembrane proteins Gn and Gc form spikes on the surface of the virus particle. They are involved in virus attachment and cell fusion. Once inside the cell, the viral membrane fuses with the endosomal membrane, and the virus genome is released. Transcription involves an RNA dependent RNA polymerase , and it occurs in the cytoplasm of the cell. Transcription of the tripartite genome is terminated by a strong hairpin loop sequence at the end of each segment. Once the virus has replicated enough, it is encapsidated. Assembly and budding of the newly synthesized virions occurs at the membranes of the Golgi apparatus . In terms of CVV alone, very little is known about the regulation of host-processes and interactions with host cells. However, CVVs Bunyamwera serogroup's two non-structural proteins play an important role in infection. Bunyamwera virus (BUNV) codes for two non-structural proteins: NSm on the medium RNA segment and NSs on the smallest RNA segment. Bunyamwera virus NSs protein is a nonessential gene that contributes to viral pathogenesis. It has been shown that in mammalian cells, NSs induces shut-off of host protein synthesis, which leads to cell death. It also counteracts the host cell antiviral response and seems to be the main virulence factor, acting at the level of transcription by inhibiting RNA polymerase II–mediated transcription. In mosquito cells neither host cell transcription nor translation are inhibited, and although so far no function for the orthobunyavirus NSs protein has been found in mosquito cells, it seems the differential behavior of NSs could be one of the factors responsible for different outcomes of infection in mammalian and mosquito cell lines. The Cache Valley virus genome is split into three parts. The three parts are called the small, medium, and large segments, based on the number of bases. The large segment encodes the L protein, which is the RNA dependent RNA polymerase. The small segment utilizes an open reading frame with alternative initiation sites to encode two proteins. Depending on the initiation site, it can either code for the protein that makes up the nucleocapsid , N, or a non-structural protein , NSs. The medium segment encodes 2 type 1 integral transmembrane glycoproteins, Gn and Gc, as well as a non-structural protein Nsm. The Gc and Gn proteins start as one precursor protein and are then cleaved cotranslationally. They are modified by N-linked glycosylation. The attachment, entry, replication, and release of CVV specifically have not been studied. However, there is information of the replication cycle for the genus orthobunyavirus, which CVV is a part of. A heterodimer of integral transmembrane proteins Gn and Gc form spikes on the surface of the virus particle. They are involved in virus attachment and cell fusion. Once inside the cell, the viral membrane fuses with the endosomal membrane, and the virus genome is released. Transcription involves an RNA dependent RNA polymerase , and it occurs in the cytoplasm of the cell. Transcription of the tripartite genome is terminated by a strong hairpin loop sequence at the end of each segment. Once the virus has replicated enough, it is encapsidated. Assembly and budding of the newly synthesized virions occurs at the membranes of the Golgi apparatus . In terms of CVV alone, very little is known about the regulation of host-processes and interactions with host cells. However, CVVs Bunyamwera serogroup's two non-structural proteins play an important role in infection. Bunyamwera virus (BUNV) codes for two non-structural proteins: NSm on the medium RNA segment and NSs on the smallest RNA segment. Bunyamwera virus NSs protein is a nonessential gene that contributes to viral pathogenesis. It has been shown that in mammalian cells, NSs induces shut-off of host protein synthesis, which leads to cell death. It also counteracts the host cell antiviral response and seems to be the main virulence factor, acting at the level of transcription by inhibiting RNA polymerase II–mediated transcription. In mosquito cells neither host cell transcription nor translation are inhibited, and although so far no function for the orthobunyavirus NSs protein has been found in mosquito cells, it seems the differential behavior of NSs could be one of the factors responsible for different outcomes of infection in mammalian and mosquito cell lines. Prior to 1956 there were no known cases of acute infections of Cache Valley virus (CVV) in humans. However antibodies against CVV have been reported. One study found neutralizing antibody to CVV in 12% of 356 persons surveyed in Maryland and Virginia in the 1960s. These results and other such serosurveys are based on nonrandom sampling and therefore often difficult to interpret. CVV disease is a neuroinvasive illness. Of the three confirmed human cases of CVV disease two resulted in non-fatal meningitis, only the first case caused fatal encephalitis and multiorgan failure. The first case was a 28-year-old man from North Carolina in 1995. It is likely he was infected with the virus via mosquitos during a deer-hunting trip. The patient's first symptoms were muscle pain, fever, chills and a headache. He began vomiting the day after the first symptoms appeared. Six days after the onset of the illness more severe symptoms appeared including confusion, tachycardia (elevated heart rate), a rash, bilateral conjunctivitis and meningismus. The next day the patient became hypotensive and delirious. Later respiratory failure, seizures and necrosis of the fingers and toes occurred. One leg was amputated because of extensive muscle and cutaneous necrosis. Seven months after the onset of the illness the patient died of pulmonary complications. The causative agent was identified as a virus in the family Bunyaviridae by electron microscopy. This was then identified genetically as CVV. Viremia was recorded seven days after the onset of fever; this is a longer period of viremia than what is normally observed in cases of Bunyaviridae infections. The second human case of CVV was a 41-year-old man from Wisconsin in October 2003. He developed an acute illness with severe nausea, vomiting, fatigue and headache. He was diagnosed with acute aseptic meningitis. After three days the patient was released from the hospital; he reported feeling fully recovered four months later, though he experienced headaches more frequently than usual. The causative agent was observed with electron microscopy as being virions morphologically similar to bunyaviruses. Nucleotide sequencing identified the virus as CVV. The third human case of CVV was a 63-year-old woman in New York, in September 2011. When she was admitted to the hospital her symptoms were fever, headache, neck stiffness and photophobia. A week before she had noticed a lesion on her arm, as this began to fade a rash developed and spread. She then developed a fever and symptoms of meningitis. The patient was discharged, but returned the next day with nausea and vomiting. She was diagnosed with aseptic meningitis. She was discharged four days later. Two months after this she reported ongoing difficulties in word finding and headaches. CVV was identified as the causative agent by PCR, sequence analysis confirmed this identification. It is likely that CVV disease is underreported. Very few human cases have been reported despite its wide geographic distribution and the large number of mosquito species that transmit it. The rarity of CVV disease diagnosis is partly due to the fact that laboratories rarely test for CVV. Therefore, the true incidence of CVV disease and its full clinical range are still unknown. Given the widespread distribution of CVV and other viruses in the same serogroup in the United States it is possible some unexplained cases of severe multiorgan failure, congenital anomalies and human viral encephalitis may be due to CVV or similar viruses. More research of such cases is needed. Cache Valley virus is the most common Orthobunyavirus in North America, and while isolated in 1956, was only linked to disease in Texas in 1987 during a large occurrence of aborted and malformed lambs in a sheep flock. The virus does not only infect sheep, however, as In 2002 a survey conducted in 22 states showed 28% of cattle expressed specific antibodies to CVV. Cache Valley virus has also been identified as a cause of fetal abnormalities in goats. Other serological surveys have also shown antibodies to CVV in domestic and wild ruminants , along with horses . Of wild ruminants, deer have a very high seroprevalence. With viraemia lasting 1 to 3 days, they are easily able to spread the virus to vectors including Culicoides midges and Aedes , Anopheles , Coquillettidia and Culiseta group mosquitoes . Therefore, deer tend to act as amplifying hosts to the virus. While the virus is able to replicate in adult animals, besides a slight febrile response in some cases, there are no known symptoms of infection. There is a quick period of viraemia before seroconversion and the infection is cleared quickly by the animal's immune system . However, if the animal is pregnant and not protected by antibodies from a previous infection, Cache Valley virus can be very lethal to a developing fetus. The symptoms the fetus develops from CVV infection are largely age dependent. At less than 28 days of gestation, the embryo usually dies and is reabsorbed by the mother. Between 28 and 45 days of gestation, infection leads to malformations in the developing fetus and occasionally leads to abortions. Early in this window, between 28 and 36 days, the virus leads to both central nervous system and musculoskeletal defects, while after 36 days of gestation infection only leads to musculoskeletal deformities. Death of the fetus usually occurs between 27 and 35 days gestation, when the central nervous system tissues are most susceptible. After 45–50 days of gestation CVV infection is not expected to cause harmful effects. After 76 days the fetus has a functioning immune system and antibodies to the virus are produced. Autopsies of infected fetuses show severe lesions in the brain and spinal column, ranging from microscopic in size to whole sections of the brain missing. In one laboratory case, the cerebral hemispheres were nothing more than fluid-filled sacs that were easily ruptured. The most common musculoskeletal deformations include arthrogryposis and greatly reduced muscle mass, with the most severe cases having torticollis , scoliosis , and kyphosis . While most affected lambs are stillborn, those that do survive are usually so weak they die within minutes of birth. During the time that they are alive, these lamb are reported to act abnormal, such as acting weak, drowsy, or walking unsteadily. When ewes were experimentally infected with Akabane virus , a teratogenic virus of the genus Orthobunyavirus closely related to Cache Valley virus, the virus was shown to replicate in the trophoblastic cells of the placenta . When the virus crossed the placenta and infected the developing fetus, it showed a tropism for the immature fetal cells of the central nervous system and skeletal muscle. Hydranencephaly has also been identified in goat kids with presumptive in utero infection with Cache Valley virus. While the virus is able to replicate in adult animals, besides a slight febrile response in some cases, there are no known symptoms of infection. There is a quick period of viraemia before seroconversion and the infection is cleared quickly by the animal's immune system . However, if the animal is pregnant and not protected by antibodies from a previous infection, Cache Valley virus can be very lethal to a developing fetus. The symptoms the fetus develops from CVV infection are largely age dependent. At less than 28 days of gestation, the embryo usually dies and is reabsorbed by the mother. Between 28 and 45 days of gestation, infection leads to malformations in the developing fetus and occasionally leads to abortions. Early in this window, between 28 and 36 days, the virus leads to both central nervous system and musculoskeletal defects, while after 36 days of gestation infection only leads to musculoskeletal deformities. Death of the fetus usually occurs between 27 and 35 days gestation, when the central nervous system tissues are most susceptible. After 45–50 days of gestation CVV infection is not expected to cause harmful effects. After 76 days the fetus has a functioning immune system and antibodies to the virus are produced. Autopsies of infected fetuses show severe lesions in the brain and spinal column, ranging from microscopic in size to whole sections of the brain missing. In one laboratory case, the cerebral hemispheres were nothing more than fluid-filled sacs that were easily ruptured. The most common musculoskeletal deformations include arthrogryposis and greatly reduced muscle mass, with the most severe cases having torticollis , scoliosis , and kyphosis . While most affected lambs are stillborn, those that do survive are usually so weak they die within minutes of birth. During the time that they are alive, these lamb are reported to act abnormal, such as acting weak, drowsy, or walking unsteadily. When ewes were experimentally infected with Akabane virus , a teratogenic virus of the genus Orthobunyavirus closely related to Cache Valley virus, the virus was shown to replicate in the trophoblastic cells of the placenta . When the virus crossed the placenta and infected the developing fetus, it showed a tropism for the immature fetal cells of the central nervous system and skeletal muscle. Hydranencephaly has also been identified in goat kids with presumptive in utero infection with Cache Valley virus. Cache Valley virus was first isolated from mosquitoes in Utah in 1956. It derives its name from Cache Valley, an agricultural valley located in northern Utah and southeast Idaho. It is endemic to North America, specifically Canada, Mexico, and the United States. The first confirmed human case happened on November 2, 1995. In Texas in 1987, CVV was described as a possible causative agent of disease in sheep. The white-tailed deer population has been identified as a potential natural reservoir . Currently, there is no vaccine or known treatment available for CVV. The most effective method of protecting ruminants from CVV is to minimize their exposure to mosquito-infested areas during and shortly after breeding season. Concerning the safety of humans, it is advised that necessary precautions be taken, such as, putting on mosquito repellent or layers of clothing, when being exposed to mosquito-infested areas.

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Crimean-Congo haemorrhagic fever

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Jean-Paul Gonzalez

Jean-Paul Joseph Gonzalez (born August 28, 1947) is a French virologist. He graduated from the Medical School of Bordeaux University (M.D., Internal Medicine) France.Gonzalez is a virologist whose main fields of research encompass the fundamentals and domains of disease emergence, viral disease and eco-epidemiology (i.e. arbovirology , viral hemorrhagic fevers ). He received his PhD in viral ecology in 1984 from the University of Clermont-Ferrand in France. He was recruited by the French Institute of Research for Development, IRD (alias ORSTOM ), and he dedicated his career to research, training, and providing expertise for developing countries across the Americas, Africa and Asia. He has led field and laboratory teams of researchers in countries such as Brazil, Central African Republic, Gabon, Laos, Senegal, Sierra-Leone, Thailand, Ukraine and more. He worked as a fellow at the Center for Disease Control and Prevention in Atlanta and Fort Collins, and as a visiting professor at the Yale Arbovirus Research Unit ( Yale University , School of Medicine). Gonzalez has been involved in high security laboratory practices and research and, early development of geographical information systems applied to infectious diseases. He and his teams have identified new pathogens for humans and animals, have developed tools and strategies for bio-surveillance, and control and prevention of highly infectious transmitted disease (i.e.: high consequence pathogens ). He has developed several scientific concepts and research strategies for health (e.g.: long lasting co-evolution of germs and hosts). He was instrumental to introduce and applied the concept of One Health in low income countries.Gonzalez was born and raised near the town of Saint Georges de Didonne in South-West of France in 1947. His father, Jesus Gonzalez, was a Spanish immigrant, born in Madrid who fled from General Franco 's regime to France during the Spanish Civil War . Jean-Paul's mother, Jeanne Charlotte Rives, was third daughter of a barrel maker from the Blaye vineyard of Bordeaux. She raised their three children (Denis, Denise and Jean-Paul).Gonzalez graduated from the Medical School of Bordeaux University in 1974. By attending the same school, he also got a Master on Tropical Medicine and Hygiene as well as a Medical Diploma of the French Commercial Navy. This was followed by a residence in French Guiana at the Hôpital André-Bouron , located on the left bank of the Maroni River on the amazonian forest. Gonzalez was in charge of the adult, pediatric, and geriatric wards, as well of the Acarouany leprosy hospital and, health control over the Maroni River border between French Guiana and Suriname . He returned to Bordeaux and took the position of associate professor of Parasitology and Fundamental Sciences at Bordeaux School of Medicine and as medical attendant at the Children Teaching Hopital (Hôpital des Enfants Malades ). He also worked at the Saint-André Teaching Hospital as a biologist. Gonzalez did its 18 months national duty as a Volunteer at the National Active Service ( VSNA ) at the Pasteur Institute of Tunis (Tunisia) where he traveled extensively for the Pasteur Institute as a WHO ( World Health Organization ) expert collecting mosquitoes' larvae and identifying imago for the surveillance of malaria in Tunisia. There he published several fundamental articles on the Tunisian endemic fauna parasites (fresh water turtles, rodents and cockroaches ). Gonzalez later spent more than ten years as laboratory chief, and then department head within the Institut Pasteur International Network (RIIP) in Bangui , Central African Republic, and in Dakar . In 1990 he was one of the first foreign doctors to work at the high containment laboratory (BSL4) in Atlanta. There he analyzed all the samples previously collected in Central Africa in search of Viral Hemorrhagic Fever traces including Ebola and Marburg, Arenavirus, Hantavirus, Crimean Congo Hemorrhagic virus and others. In the late 90s he began working as a professor of Epidemiology and Public Health at the Yale School of Medicine; focusing on arboviruses and hemorrhagic viral fevers including Argentinian, Bolivian, Brazilian, Venezuelan, and Dengue fevers among others. Since the early 1980s to date he continues to study, train and give expertise on Viral Hemorrhagic fevers including, among others, a follow up on Ebola fever (alias Ebolavirus Disease) and other high consequence pathogens. From 2008 to 2012 he was appointed as General Director of the International Center of Medical Research of Franceville, Republic of Gabon (CIRMF). Appointed there by the French Ministry of Europe and Foreign Affairs and, then nominated at the direction position by the Gabon President (H.E. Omar Bongo ), he intensively participate to the development of innovative field of research of interest for Gabon' public health, including preparedness and response of high consequent pathogens, One Health approach as a tool for public health improvement, co-founded the Central African Network for Sickle Cell Study (REDAC), among other advancements. In 2012, he joined Metabiota , Inc. as Senior Staff Scientist, where he uses his expertise on emerging viral disease, biosafety, biosecurity and bio-surveillance, and trains scientists from low income countries of Africa and Eastern Europe. In 2017 he was appointed at Deputy Director of the Center of Excellence for Animal and Zoonotic Diseases (CEEZAD ), Kansas State University (KSU). Where his work focuses extensively on zoonosis , perpetuating also his engagement on One Health approach (One Health News Letter) and Global Health. He has published more than 250 peers reviewed (NCBI ) scientific papers, books and book chapters.

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Crimean-Congo haemorrhagic fever

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Joseph Mugisha

Joseph Y.T. Mugisha is a Ugandan mathematician (specialising in biomathematics), academician and academic administrator . Currently he is a Professor of Mathematics and Principal of the College of Natural Sciences, a constituent college of Makerere University . Makerere University is the Oldest University in Uganda.He was born in 1960 in Bushenyi district , Western Uganda . Professor Mugisha received his PhD in Bio-mathematics in 2000 from Makerere university. Prior to that he was awarded a Masters of Science(Bio-mathematics) in 1992 and a Bachelors of Science in Education from Makerere University. He attended Mbarara High School for his Secondary Education; and Masheruka Primary School for foundation Education.Before his appointment as the Principal of the College of Natural Sciences (CONAS), he was the Dean-Faculty of Science from 2009 to 2010, in which position he led the process of conversion of the faculty to a college. He held the Principal post initially in acting capacity (2010 to 2011) before substantive appointment in 2012. He has also served as the Acting Deputy Vice Chancellor[Academic Affairs] at Makerere University. Professor Mugisha joined Makerere University as a Teaching Assistant in 1987 rising through the ranks to Professorship in 2008. He has also served the University in various leadership and management capacities; Acting Director Institute of Computer Science - Makerere University from August to December 2003; Deputy Director Institute of Computer Science - Makerere university from 2003 to August 2005. He is also a member of the Makerere University Senate which is the highest academic decisions making body of the University, he has been appointed to several boards and committees within the University. Professor Mugisha has taught courses at Undergraduate and Graduate level. He has supervised and mentored over 40 students at graduate level(both PhD and MSc.) in the region. He is an International Researcher and Examiner with strong links to several universities in Eastern, Central and Southern Africa. He has served as a Reviewer of several International Journals like Mathematical Biosciences, Southern Journal of Sciences, Mathematical Biosciences and Engineering, Mathematical Modelling and Analysis, Ecological Modelling, Computers and Mathematics with Application, Computational and Applied Mathematics, Mathematical and Computer Modelling, among others. Professor Mugisha is a founder member and the current President of the African Society for Bio-mathematics since 2009. He has been a member of the American Mathematical Society, Ugandan Mathematical Society, Ugandan Biometric Society and is a Fellow of the Ugandan National Academy of Sciences [UNAS]. Professor Mugisha is widely published in over 50 articles in International Journals. His major research interest is in the application of mathematics in biology and biomedical processes with special emphasis on epidemiological and ecological modeling. He has co - organized, attended and facilitated at various conferences, workshops and seminars nationally and internationally. He is a member Kyambogo University Council , and board member of the Uganda National Council for Science and Technology council.

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Crimean-Congo haemorrhagic fever

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O'nyong'nyong virus

The o'nyong'nyong virus ( ONNV ) was first isolated by researchers at the Uganda Virus Research Institute in Entebbe , Uganda , during a large outbreak of a disease in 1959 that resembled dengue fever . ONNV is a togavirus (family Togaviridae), genus Alphavirus , is closely related to the chikungunya and Igbo Ora viruses, and is a member of the Semliki Forest antigenic complex. The name was given to the disease by the Acholi tribe during the 1959 outbreak. The name comes from the Nilotic language of Uganda and Sudan and means "weakening of the joints". The virus can infect humans and may cause disease. Common symptoms of infection with the virus are polyarthritis , rash and fever . Other symptoms include eye pain, chest pain, lymphadenitis and lethargy. The disease is self-limiting . No fatalities due to infection are known.ONNV has at least three major subtypes, or strains, the genomic sequences of which are currently available on genome databases. ONNV is transmitted by bites from an infected mosquito . It is the only virus whose primary vectors are anopheline mosquitoes ( Anopheles funestus and Anopheles gambiae ) [ citation needed ] .ONNV has at least three major subtypes, or strains, the genomic sequences of which are currently available on genome databases.ONNV is transmitted by bites from an infected mosquito . It is the only virus whose primary vectors are anopheline mosquitoes ( Anopheles funestus and Anopheles gambiae ) [ citation needed ] .There have been two epidemics of o'nyong'nyong fever. The first occurred from 1959 to 1962, spreading from Uganda to Kenya , Tanzania , Zaire ( Democratic Republic of the Congo ), Malawi and Mozambique , and affecting over two million people, one of the largest arbovirus epidemics ever recorded. The first virus isolates were obtained during this outbreak from mosquitoes and human blood samples collected from Gulu in northern Uganda in 1959. The second epidemic in 1996–1997 was confined to Uganda. The 35-year hiatus between the two outbreaks and evidence of an outbreak in 1904–1906 in Uganda indicate a 30–50 year cycle for epidemics. In 2013, ONNV was confirmed as the cause of disease in a 60-year-old German woman who became infected while traveling in East Africa. In 2015–2016 there was a minor outbreak in Uganda with 51 suspected cases. [ citation needed ] There has been a minor outbreak in Mombasa (Kenya) and the County Government of Mombasa issued a warning. A 2015 study indicated that ONNV is endemic in coastal East Africa, along with chikungunya virus.

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Crimean-Congo haemorrhagic fever

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Bunyamwera orthobunyavirus

Bunyamwera virus Bunyamwera orthobunyavirus ( BUNV ) is a negative-sense, single-stranded enveloped RNA virus . It is assigned to the Orthobunyavirus genus , in the Bunyavirales order. Bunyamwera orthobunyavirus can infect both humans and Aedes aegypti (yellow fever mosquito). It is named for Bunyamwera , a town in western Uganda , where it was isolated in 1943. Reassortant viruses derived from Bunyamwera orthobunyavirus , such as Ngari virus , have been associated with large outbreaks of viral haemorrhagic fever in Kenya and Somalia . The genetic structure of Bunyamwera orthobunyavirus is typical for Bunyavirales viruses, which are an order of enveloped negative-sense, single-stranded RNA viruses with a genome split into three parts—Small (S), Middle (M), and Large (L). The L RNA segment encodes an RNA-dependent RNA polymerase (L protein), the M RNA segment encodes two surface glycoproteins (Gc and Gn) and a nonstructural protein (NSm), while the S RNA segment encodes a nucleocapsid protein (N) and, in an alternative overlapping reading frame , a second nonstructural protein (NSs). The genomic RNA segments are encapsidated by copies of the N protein in the form of ribonucleoprotein (RNP) complexes. The N protein is the most abundant protein in virus particles and infected cells and, therefore, the main target in many serological and molecular diagnostics. In humans, Bunyamwera orthobunyavirus causes Bunyamwera fever.

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Crimean-Congo haemorrhagic fever

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Mosquito-borne disease

Mosquito-borne diseases or mosquito-borne illnesses are diseases caused by bacteria, viruses or parasites transmitted by mosquitoes . Nearly 700 million people get a mosquito-borne illness each year, resulting in over 725,000 deaths. Diseases transmitted by mosquitoes include malaria , dengue , West Nile virus , chikungunya , yellow fever , filariasis , tularemia , dirofilariasis , Japanese encephalitis , Saint Louis encephalitis , Western equine encephalitis , Eastern equine encephalitis , Venezuelan equine encephalitis , Ross River fever , Barmah Forest fever , La Crosse encephalitis , and Zika fever , as well as newly detected Keystone virus and Rift Valley fever . In January 2024, an Australian research group proved that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer is transmitted by mosquitos. This is the first described mosquito-borne transmission of a bacterial disease. There is no evidence as of April 2020 that COVID-19 can be transmitted by mosquitoes, and it is extremely unlikely this could occur. The female mosquito of the genus Anopheles may carry the malaria parasite . Four different species of protozoa cause malaria: Plasmodium falciparum , Plasmodium malariae , Plasmodium ovale and Plasmodium vivax (see Plasmodium ). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by the World Health Organization (WHO). The death toll increased to one million as of 2018 according to the American Mosquito Control Association. In January 2024, a publication by an Australian research group demonstrated significant genetic similarity between Mycobacterium ulcerans in humans and possums, compared to PCR screening of M. ulcerans from trapped Aedes notoscriptus mosquitoes, and concluded that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer , is transmitted by mosquitos. Botflies are known to parasitize humans or other mammalians, causing myiasis , and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly Dermatobia hominis attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of the larvae. [ citation needed ] Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis ) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability. [ citation needed ] The viral diseases yellow fever , dengue fever , Zika fever and chikungunya are transmitted mostly by Aedes aegypti mosquitoes. [ citation needed ] Other viral diseases like epidemic polyarthritis , Rift Valley fever , Ross River fever , St. Louis encephalitis , West Nile fever , Japanese encephalitis , La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occur in the United States where they cause disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma, and death. Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses . West Nile virus was accidentally introduced into the US in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006. Other species of Aedes as well as Culex and Culiseta are also involved in the transmission of disease. [ citation needed ] Myxomatosis is spread by biting insects, including mosquitoes. The female mosquito of the genus Anopheles may carry the malaria parasite . Four different species of protozoa cause malaria: Plasmodium falciparum , Plasmodium malariae , Plasmodium ovale and Plasmodium vivax (see Plasmodium ). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by the World Health Organization (WHO). The death toll increased to one million as of 2018 according to the American Mosquito Control Association. In January 2024, a publication by an Australian research group demonstrated significant genetic similarity between Mycobacterium ulcerans in humans and possums, compared to PCR screening of M. ulcerans from trapped Aedes notoscriptus mosquitoes, and concluded that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer , is transmitted by mosquitos. Botflies are known to parasitize humans or other mammalians, causing myiasis , and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly Dermatobia hominis attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of the larvae. [ citation needed ]Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis ) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability. [ citation needed ]The viral diseases yellow fever , dengue fever , Zika fever and chikungunya are transmitted mostly by Aedes aegypti mosquitoes. [ citation needed ] Other viral diseases like epidemic polyarthritis , Rift Valley fever , Ross River fever , St. Louis encephalitis , West Nile fever , Japanese encephalitis , La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occur in the United States where they cause disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma, and death. Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses . West Nile virus was accidentally introduced into the US in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006. Other species of Aedes as well as Culex and Culiseta are also involved in the transmission of disease. [ citation needed ] Myxomatosis is spread by biting insects, including mosquitoes. A mosquito's period of feeding is often undetected; the bite only becomes apparent because of the immune reaction it provokes. When a mosquito bites a human, it injects saliva and anti-coagulants . With the initial bite to an individual, there is no reaction, but with subsequent bites, the body's immune system develops antibodies . The bites become inflamed and itchy within 24 hours. This is the usual reaction in young children. With more bites, the sensitivity of the human immune system increases, and an itchy red hive appears in minutes where the immune response has broken capillary blood vessels and fluid has collected under the skin. This type of reaction is common in older children and adults. Some adults can become desensitized to mosquitoes and have little or no reaction to their bites, while others can become hyper-sensitive with bites causing blistering, bruising, and large inflammatory reactions, a response known as skeeter syndrome . One study found Dengue virus and Zika virus altered the skin bacteria of rats in a way that caused their body odor to be more attractive to mosquitoes. Symptoms of illness are specific to the type of viral infection and vary in severity, based on the individuals infected. Symptoms vary in severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare. Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those with cancer, diabetes, hypertension, and kidney disease. Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal. People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications. Symptoms vary in severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare. Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those with cancer, diabetes, hypertension, and kidney disease. Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal. People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications. Mosquitoes carrying such arboviruses stay healthy because their immune systems recognizes the virions as foreign particles and "chop off" the virus' genetic coding, rendering it inert. Human infection with a mosquito-borne virus occurs when a female mosquito bites someone while its immune system is still in the process of destroying the virus's harmful coding. [ clarification needed ] It is not completely known how mosquitoes handle eukaryotic parasites to carry them without being harmed. Data has shown that the malaria parasite Plasmodium falciparum alters the mosquito vector's feeding behavior by increasing frequency of biting in infected mosquitoes, thus increasing the chance of transmitting the parasite. The mechanism of transmission of this disease starts with the injection of the parasite into the victim's blood when malaria-infected female Anopheles mosquitoes bite into a human being. The parasite uses human liver cells as hosts for maturation where it will continue to replicate and grow, moving into other areas of the body via the bloodstream. The spread of this infection cycle then continues when other mosquitoes bite the same individual. The result will cause that mosquito to ingest the parasite and allow it to transmit the Malaria disease into another person through the same mode of bite injection. Flaviviridae viruses transmissible via vectors like mosquitoes include West Nile virus and yellow fever virus, which are single stranded, positive-sense RNA viruses enveloped in a protein coat. Once inside the host's body, the virus will attach itself to a cell's surface through receptor-mediated endocytosis. This essentially means that the proteins and DNA material of the virus are ingested into the host cell. The viral RNA material will undergo several changes and processes inside the host's cell so that it can release more viral RNA that can then be replicated and assembled to infect neighboring host cells. Mosquito-borne flaviviruses also encode viral antagonists to the innate immune system in order to cause persistent infection in mosquitoes and a broad spectrum of diseases in humans. The data on transmissibility via insect vectors of hepatitis C virus, also belonging to family Flaviviridae (as well as for hepatitis B virus, belonging to family Hepadnaviridae ) are inconclusive. WHO states that "There is no insect vector or animal reservoir for HCV", while there are experimental data supporting at least the presence of [PCR]-detectable hepatitis C viral RNA in Culex mosquitoes for up to 13 days. Currently, there are no specific vaccine therapies for West Nile virus approved for humans; however, vaccines are available and some show promise for animals, as a means to intervene with the mechanism of spreading such pathogens. Doctors can typically identify a mosquito bite by sight. A doctor will perform a physical examination and ask about medical history as well as any travel history. Be ready to give details on any international trips, including the dates you were traveling, the countries you visited and any contact you had with mosquitoes. Diagnosing dengue fever can be difficult, as its symptoms often overlap with many other diseases such as malaria and typhoid fever . Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment. Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation. A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test. Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months. Diagnosing dengue fever can be difficult, as its symptoms often overlap with many other diseases such as malaria and typhoid fever . Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment. Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation. A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test. Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months. There is a re-emergence of mosquito vectored viruses (arthropod-borne viruses) called arboviruses carried by the Aedes aegypti mosquito. Examples are the Zika virus, chikungunya virus, yellow fever and dengue fever. The re-emergence of the viruses has been at a faster rate, and over a wider geographic area, than in the past. The rapid re-emergence is due to expanding global transportation networks, the mosquito's increasing ability to adapt to urban settings, the disruption of traditional land use and the inability to control expanding mosquito populations. Like malaria, arboviruses do not have a vaccine. (The only exception is yellow fever.) Prevention is focused on reducing the adult mosquito populations, controlling mosquito larvae and protecting individuals from mosquito bites. Depending on the mosquito vector, and the affected community, a variety of prevention methods may be deployed at one time. The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors Anopheles gambiae and Anopheles funestus which carry malaria. Because the Anopheles gambiae feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported Anopheles vector resistance to pyrethroid insecticides. Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the Aedes aegypti mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes. There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with icaridin or DEET is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes. There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine , and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV . The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015. To date, there are relatively few vaccines against mosquito-borne diseases, this is due to the fact that most viruses and bacteria caused by mosquitos are highly mutatable. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases. The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the Aedes aegypti mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention. The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors Anopheles gambiae and Anopheles funestus which carry malaria. Because the Anopheles gambiae feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported Anopheles vector resistance to pyrethroid insecticides. Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the Aedes aegypti mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes. There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with icaridin or DEET is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes. There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine , and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV . The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015. To date, there are relatively few vaccines against mosquito-borne diseases, this is due to the fact that most viruses and bacteria caused by mosquitos are highly mutatable. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases. The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the Aedes aegypti mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention. Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation . Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net . Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs. Dengue fever occurs via Aedes aegypti mosquito (it acts as a vector). Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics . Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used. There are no treatment modalities for acute and chronic chikungunya that currently exist. Most treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis . In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains. The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies , the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world. Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation . Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net . Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs. Dengue fever occurs via Aedes aegypti mosquito (it acts as a vector).Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics . Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used. There are no treatment modalities for acute and chronic chikungunya that currently exist. Most treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis . In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains. The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies , the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world. Mosquito-borne diseases, such as dengue fever and malaria , typically affect developing countries and areas with tropical climates. Mosquito vectors are sensitive to climate changes and tend to follow seasonal patterns. Between years there are often dramatic shifts in incidence rates. The occurrence of this phenomenon in endemic areas makes mosquito-borne viruses difficult to treat. Dengue fever is caused by infection through viruses of the family Flaviviridae. The illness is most commonly transmitted by Aedes aegypti mosquitoes in tropical and subtropical regions. Dengue virus has four different serotypes, each of which are antigenically related but have limited cross-immunity to reinfection. Although dengue fever has a global incidence of 50–100 million cases, only several hundreds of thousands of these cases are life-threatening. The geographic prevalence of the disease can be examined by the spread of Aedes aegypti . Over the last twenty years, there has been a geographic spread of the disease. Dengue incidence rates have risen sharply within urban areas which have recently become endemic hot spots for the disease. The recent spread of Dengue can also be attributed to rapid population growth, increased coagulation in urban areas, and global travel. Without sufficient vector control, the dengue virus has evolved rapidly over time, posing challenges to both government and public health officials. [ citation needed ] Malaria is caused by a protozoan called Plasmodium falciparum . P. falciparum parasites are transmitted mainly by the Anopheles gambiae complex in rural Africa. In just this area, P. falciparum infections comprise an estimated 200 million clinical cases and 1 million annual deaths. 75% of individuals affected in this region are children. As with dengue, changing environmental conditions have led to novel disease characteristics. Due to increased illness severity, treatment complications, and mortality rates, many public health officials concede that malaria patterns are rapidly transforming in Africa. Scarcity of health services, rising instances of drug resistance, and changing vector migration patterns are factors that public health officials believe contribute to malaria's dissemination. Climate heavily affects mosquito vectors of malaria and dengue. Climate patterns influence the lifespan of mosquitos as well as the rate and frequency of reproduction. Climate change impacts have been of great interest to those studying these diseases and their vectors. Additionally, climate impacts mosquito blood feeding patterns as well as extrinsic incubation periods. Climate consistency gives researchers an ability to accurately predict annual cycling of the disease but recent climate unpredictability has eroded researchers' ability to track the disease with such precision.In many insect species, such as Drosophila melanogaster , researchers found that a natural infection with the bacteria strain Wolbachia pipientis increases the fitness of the host by increasing resistance to RNA viral infections. Robert L. Glaser and Mark A. Meola investigated Wolbachia -induced resistance to West Nile virus (WNV) in Drosophila melanogaster (fruit flies). Two groups of fruit flies were naturally infected with Wolbachia . Glaser and Meola then cured one group of fruit flies of Wolbachia using tetracycline. Both the infected group and the cured groups were then infected with WNV. Flies infected with Wolbachia were found to have a changed phenotype that caused resistance to WNV. The phenotype was found to be caused by a "dominant, maternally transmitted, cytoplasmic factor". The WNV-resistance phenotype was then reversed by curing the fruit flies of Wolbachia . Since Wolbachia is also maternally transmitted, it was found that the WNV-resistant phenotype is directly related to the Wolbachia infection. West Nile virus is transmitted to humans and animals through the Southern house mosquito, Culex quinquefasciatus . Glaser and Meola knew vector compatibility could be reduced through Wolbachia infection due to studies done with other species of mosquitoes, mainly, Aedes aegypti . Their goal was to transfer WNV resistance to Cx. quinquefasciatus by inoculating the embryos of the mosquito with the same strain of Wolbachia that naturally occurred in the fruit flies. Upon infection, Cx. quinquefasciatus showed an increased resistance to WNV that was transferable to offspring. The ability to genetically modify mosquitoes in the lab and then have the infected mosquitoes transmit it to their offspring showed that it was possible to transmit the bacteria to wild populations to decrease human infections. [ citation needed ] In 2011, Ary Hoffmann and associates produced the first case of Wolbachia -induced arbovirus resistance in wild populations of Aedes aegypti through a small project called Eliminate Dengue: Our Challenge. This was made possible by an engineered strain of Wolbachia termed w Mel that came from D. melanogaster . The transfer of w Mel from D. melanogaster into field-caged populations of the mosquito Aedes aegypti induced resistance to dengue, yellow fever, and chikungunya viruses. Although other strains of Wolbachia also reduced susceptibility to dengue infection, they also put a greater demand on the fitness of Ae. aegypti . w Mel was different in that it was thought to only cost the organism a small portion of its fitness. w Mel-infected Ae. aegypti were released into two residential areas in the city of Cairns, Australia over a 14-week period. Hoffmann and associates, released a total of 141,600 infected adult mosquitoes in Yorkeys Knob suburb and 157,300 in Gordonvale suburb. After release, the populations were monitored for three years to record the spread of w Mel. Population monitoring was gauged by measuring larvae laid in traps. At the beginning of the monitoring period but still within the release period, it was found that w Mel-infected Ae. aegypti had doubled in Yorkeys Knob and increased 1.5-fold in Gordonvale. Uninfected Ae. aegypti populations were in decline. By the end of the three years, w Mel-infected Ae. aegypti had stable populations of about 90%. However, these populations were isolated to the Yorkeys Knob and Gordonvale suburbs due to unsuitable habitat surrounding the neighborhoods. Although populations flourished in these areas with nearly 100% transmission, no signs of spread were noted, proving disappointing for some. Following this experiment, Tom L. Schmidt and his colleagues conducted an experiment releasing Wolbachia -infected Aedes aegypti using different site selection methods occurred in different areas of Cairns during 2013. The release sites were monitored over two years. This time the release was done in urban areas that were adjacent to adequate habitat to encourage mosquito dispersal. Over the two years, the population doubled, and spatial spread was also increased, unlike the first release, giving ample satisfactory results. By increasing the spread of the Wolbachia -infected mosquitoes, the researchers were able to establish that population of a large city was possible if the mosquitoes were given adequate habitat to spread into upon release in different local locations throughout the city. In both of these studies, no adverse effects on public health or the natural ecosystem occurred. This made it an extremely attractive alternative to traditional insecticide methods given the increased pesticide resistance occurring from heavy use. From the success seen in Australia, the researchers were able to begin operating in more threatened portions of the world. The Eliminate Dengue program spread to 10 countries throughout Asia, Latin America, and the Western Pacific blooming into the non-profit organization, World Mosquito Program, as of September 2017. They still use the same technique of infecting wild populations of Ae. aegypti as they did in Australia, but their target diseases now include Zika, chikungunya and yellow fever as well as dengue. Although not alone in their efforts to use Wolbachia- infected mosquitoes to reduce mosquito-borne disease, the World Mosquito Program method is praised for being self-sustaining in that it causes permanent phenotype change rather than reducing mosquito populations through cytoplasmic incompatibility through male-only dispersal.

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Crimean-Congo haemorrhagic fever

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Alkhurma virus

Alkhurma virus ( ALKV ) ( Arabic : فيروس الخر٠ة ) is a zoonotic virus of the Flaviviridae virus family (class IV). ALKV causes Alkhurma hemorrhagic fever ( AHF ), or alternatively termed as Alkhurma hemorrhagic fever virus, and is mainly based in Saudi Arabia . After an incubation period lasting as short as 2–4 days or as long as 8 days, people with AHF develop symptoms including fever, headache, joint pain , muscle pain , vomiting, a loss of appetite , feeling of great discomfort , and chills. Less than 10% of people develop severe neurologic, central nervous system, and hemorrhagic symptoms, such as purpura, epitasis, hallucinations , disorientation , convulsions , and life-threatening epistaxis . Elevated liver enzymes , leukopenia, proteinuria and thrombocytopenia, which leads to hemorrhagic fever and encephalitis (which can result in death), have been found in hospitalized patients. The ALKV prototype strain 1776 was retrieved from a person in Saudi Arabia during the 1990s. It was found to contain over 10,000 nucleotides , with a single ORF encoding over 3,000 amino acid polyproteins. The AnhC, PrM, M, NS2A, NS2B, NS3, NS4A, 2K, NS4B and NS5 proteins are all of the same length. ALKV owns the largest polyprotein of all TB-flaviviruses calculated as of yet. ALKV has been found to be closely related to the Kyasanur Forest disease (KFD), with which it shares 89% nucleotide sequence homology. Close similarities indicate that these viruses diverged 700 years ago. Related viruses include Omsk hemorrhagic fever and Royal Farm virus .Laboratory diagnosis of ALKV can be performed in the early stages of the illness by molecular detection of PCR or virus isolation from the blood. Serologic testing using enzyme-linked immunosorbent serologic assay (ELISA) can be made afterward. Treatment consists of supportive therapy which balances the person's fluids and electrolytes, oxygen status and blood pressure monitored and maintained, and additional treatment for any further complications. The mortality rate of hospitalized patients ranges from 1 to 20%. Due to limited information pertaining to ALKV, no specific treatment, such as a vaccine , has been created or made readily available. The best measures for combating ALKV are basic tick bite prevention, such as using tick repellents and avoiding regions where ticks are found in abundance, and raising awareness. Limiting non-casual contact with livestock and domestic animals is also another way of prevention. Individuals should appropriately check for attached ticks and remove them as soon as possible if found. Tick collars for domestic animals and the use of acaricides are efficient in killing ticks on livestock. People working with animals or animal products in farms or slaughterhouses should refrain from making unprotected contact with the blood, tissues, or fluids (such as consuming unpasteurized milk ) of any potentially infected animal. The route of transmission for ALKV is not fully understood and is filled with huge knowledge gaps, though camels and sheep have been linked to be the natural hosts of this virus. There appears to be more than one possible route of transmission seen in people who have become infected with this virus: one or more bites by an infected tick, crushing an infected tick with unprotected fingers, ingestion of unpasteurised camel milk , or entry via a skin wound. There is evidence pointing to the sand tampan, Ornithodoros savignyi , as the vector. No cases of human-human transmission of AHF have ever been recorded. The geographic distribution of the virus has extended beyond Saudi Arabia; reports of ALKV have been documented in countries where there is no endemic vector of the disease, such as Egypt , Djibouti , and India . In a 2014 case study, researchers found that most cases of the virus have been reported from the Najran Region , where agriculture is heavily emphasised. [ citation needed ] As a response to the troubling illness, the KSA (Kingdom of Saudi Arabia) is treating ALKV as one of the nationally notifiable diseases in the country. An effective surveillance system was established by the Ministry of Health , where any suspected case of ALKV must be reported immediately. Three forms must be filled out to properly ensure the virus is being sufficiently monitored: A suspect case form, an epidemiological investigation form, and a laboratory requisition form. The hospitals and health centers, either governmental or private, report the potential ALKV case to the desk officers in charge of viral hemorrhagic fevers at the Directorate of Health Affairs in their respective region. Afterward, the desk officer forwards the report to the Directorate of Infectious Diseases at the Preventive Medicine Department at the Ministry of Health. Before entering the case into the database system, the desk officer in charge of AHFV reviews the case reports for accuracy and completion. Subsequently, the desk officer at the Ministry of Health formulates daily reports for the higher directors at the Ministry of Health and forwards them as feedback to the regions and their respective health units. In 2018, the tick species H. rufipes , another possible vector for this virus, has been found to be infecting migratory birds in Europe. This virus was first isolated from the blood of a 32-year-old male butcher at Dr. Soliman Fakeeh Hospital , Saudi Arabia during the 1990s, who became sick with an acute, fatal hemorrhagic fever after slaughtering a sheep imported from the small city of Alkhurma , Mecca province . Since then, over 40 cases of ALKV, with case fatality rates less than 1%, have been reported. ALKV is classified as a BSL-3 or BSL-4 agent, depending on the country's regulations.

Wiki

Crimean-Congo haemorrhagic fever

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Dabie bandavirus

SFTS virus SFTS phlebovirus Dabie mountain virus SFTS bunyavirus Huaiyangshan banyangvirus Dabie bandavirus , also called SFTS virus , is a tick-borne virus in the genus Bandavirus in the family Phenuiviridae , order Bunyavirales . The clinical condition it caused is known as severe fever with thrombocytopenia syndrome (SFTS). SFTS is an emerging infectious disease that was first described in northeast and central China 2009 and now has also been discovered in Japan, South Korea, Vietnam and Taiwan in 2015. SFTS has a fatality rate of 12% and as high as over 30% in some areas. The major clinical symptoms of SFTS are fever, vomiting, diarrhea, multiple organ failure, thrombocytopenia (low platelet count), leukopenia (low white blood cell count) and elevated liver enzyme levels. Another outbreak occurred in East China in the early half of 2020.In 2009, Xue-jie Yu and colleagues isolated the SFTS virus (SFTSV) from SFTS patients' blood. The genome has been sequenced. There are three segments—large (L), medium (M) and small (S). Five proteins have been identified—an RNA dependent RNA polymerase (RdRp), a glycoprotein N (Gn), a glycoprotein C (Gc), a nuclear protein (NP) and a non structural protein (NSs). [ citation needed ] The L segment encodes the RNA polymerase with 2084 amino acid residues. [ citation needed ] The M segment encodes one open reading frame encoding 1073 amino acid precursors of glycoproteins (Gn and Gc). [ citation needed ] The S segment has 1746 nucleotides of ambisense RNA encoding two proteins, the N and NSs proteins. These lie in opposite orientations and are separated by a 54 nucleotide intergenic region. Five genotypes (A–E) have been identified. Strains from China could be grouped into all five genotypes while isolates from South Korea lay in three (types A, D and E) and those from Japan only in one (type E). The virus appears to have originated in the Dabie Mountains in central China between 1918 and 1995. [ citation needed ] Among bunyaviruses, it appears to be more closely related to the Uukuniemi virus serogroup than to the Sandfly fever group. It is a member of the Bhanja virus serocomplex. SFTSV is a tick-borne virus; it is not clear whether it can be transmitted by other blood-sucking arthropods. It can infect many mammalian hosts, including cats , mice , hedgehogs , weasels , brushtail possums and yaks . Humans appear to be accidental hosts, and play no essential role in the life cycle of SFTSV. SFTSV has been detected from the ixodid tick , Haemaphysalis longicornis , Ixodes nipponensis , Amblyomma testudinarium and Rhipicephalus microplus . In addition to tick bite, SFTSV can be transmitted from person to person through contact with blood or mucus of an infected person. This virus has been found in the Chinese provinces of Anhui , Henan , Hubei , Jiangsu , Liaoning and Shandong . SFTS occurs in rural areas, from March to November, and a majority of cases are found from April to July. [ citation needed ] The virus has also been found in South Korea, Japan, Vietnam and Taiwan.

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Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Myxomatosis/html

Myxomatosis

Myxomatosis is a disease caused by Myxoma virus , a poxvirus in the genus Leporipoxvirus . The natural hosts are tapeti ( Sylvilagus brasiliensis ) in South and Central America, and brush rabbits ( Sylvilagus bachmani ) in North America. The myxoma virus causes only a mild disease in these species, but causes a severe and usually fatal disease in European rabbits ( Oryctolagus cuniculus ). Myxomatosis is an example of what occurs when a virus jumps from a species adapted to the virus to a naive host, and has been extensively studied for this reason. [ citation needed ] The virus was intentionally introduced in Australia, France, and Chile in the 1950s to control wild European rabbit populations. [ citation needed ]Myxoma virus is in the genus Leporipoxvirus (family Poxviridae ; subfamily Chordopoxvirinae ). Like other poxviruses, myxoma viruses are large DNA viruses with linear double-stranded DNA. Virus replication occurs in the cytoplasm of the cell. The natural hosts are tapeti ( Sylvilagus brasiliensis ) in South and Central America, and brush rabbits ( Sylvilagus bachmani ) in North America. The myxoma virus causes only a mild disease in these species, with signs limited to the formation of skin nodules. Myxomatosis is the name of the severe and often fatal disease in European rabbits caused by the myxoma virus. Different strains exist which vary in their virulence. The Californian strain, which is endemic to the west coast of the United States and Baja in Mexico, is the most virulent, with reported case fatality rates of 100%. The South American strain, present in South America and Central America, is slightly less virulent, with reported case fatality rates of 99.8%. Strains present in Europe and Australia have become attenuated, with reported case fatality rates of 50–95%. While wild rabbits in Europe and Australia have developed some immunity to the virus, this is not generally true of pet rabbits. Myxomatosis is transmitted primarily by insects. Disease transmission commonly occurs via mosquito [ which? ] or flea bites, but can also occur via the bites of flies and lice, as well as arachnid mites. The myxoma virus does not replicate in these arthropod hosts, but is physically carried by biting arthropods from one rabbit to another. Seasonality is driven by the availability of arthropod vectors and the proximity of infected wild rabbits. The myxoma virus can also be transmitted by direct contact. Infected rabbits shed the virus in ocular and nasal secretions and from areas of eroded skin. The virus may also be present in semen and genital secretions. Poxviruses are fairly stable in the environment and can be spread by contaminated objects such as water bottles, feeders, caging, or people's hands. They are resistant to drying but are sensitive to some disinfectants. A laboratory study in which European rabbits received intradermal injections of a South American strain of the myxoma virus demonstrated the following progression of disease. Initially the virus multiplied in the skin at the site of inoculation. Approximately two days following inoculation the virus was found in nearby lymph nodes, and at three days it was found in the bloodstream and abdominal organs. At approximately four days the virus was isolated from non-inoculated skin as well as from the testes. Slight thickening of the eyelids and the presence of virus in conjunctival fluid was detectable on day five. Testicular engorgement was noticed on day six. The clinical signs of myxomatosis depend on the strain of virus, the route of inoculation, and the immune status of the host. Signs of the classic nodular form of the disease include a subcutaneous mass at the site of inoculation, swelling and edema of the eyelids and genitals, a milky or purulent ocular discharge, fever, lethargy, depression, and anorexia. [ citation needed ] According to Meredith (2013), the typical time course of the disease is as follows: In peracute disease with a highly virulent strain, death may occur within 5 to 6 days of infection with minimal clinical signs other than the conjunctivitis . Death usually occurs between days 10 and 12. Highly virulent strains, such as those present in North and South America, have essentially 100% case fatality rates. In rabbits infected with attenuated, less virulent strains of the virus, the lesions seen are more variable and generally milder, and the time course is delayed and prolonged. Many rabbits will survive and the cutaneous lesions gradually scab and fall off, leaving scarring. A milder form of the disease is also seen in previously vaccinated domestic rabbits that have partial immunity. Vaccinated rabbits often present with localized scabbed lesions, frequently on the bridge of the nose and around the eyes, or multiple cutaneous masses over the body. They are often still bright and alert, and survive with nursing care. Respiratory signs are a common finding in rabbits that survive the first stages of myxomatosis. Mucopurulent nasal discharge occurs, leading to gasping and stertorous respiration with extension of the head and neck. Secondary bacterial pneumonia occurs in many cases. Chronic respiratory disease, such as nasal discharge, is common in surviving rabbits. Even in apparently recovered rabbits, it is not unusual to find lung lobes filled with fluid rather than air at necropsy . Since the 1970s an "amyxomatous" form of the disease has been reported in Europe which lacks the cutaneous nodules typical of myxomatosis. This form is clinically milder and generally nonlethal. Respiratory signs, including clear or purulent nasal discharge, predominate. Perineal edema, swollen eyelids, and purulent blepharoconjunctivitis are generally still present. This form has been observed in wild rabbits, but is significant mainly in farmed rabbits. Diagnosis of myxomatosis in European rabbits is often made on the basis of the characteristic clinical appearance. If a rabbit dies without exhibiting the classic signs of myxomatosis, or if further confirmation is desired, a number of laboratory tests are available. Historically these have included histopathology , electron microscopy , and virus isolation . Histopathologic examination of affected skin typically shows undifferentiated mesenchymal cells within a matrix of mucin , inflammatory cells, and edema . Intracytoplasmic inclusions may be seen in the epidermis and in conjunctival epithelium. Negative-stain electron microscopic examination can also be used for diagnosis due to the large size and distinctive structure of poxviruses. This method allows rapid visualization of poxviruses, but does not allow specific verification of virus species or variants. Virus isolation remains the "gold standard" against which other methods of virus detection are compared. Theoretically at least, a single viable virus present in a specimen can be grown in cultured cells, thus expanding it to produce enough material to permit further detailed characterization. The more recent development of molecular methods such as polymerase chain reaction (PCR) and real-time polymerase chain reaction assays has created faster and more accurate methods of myxoma virus identification. Real-time PCR simplifies the diagnosis of myxomatosis by allowing nasal, ocular, or genital swabs to be quickly tested. It can also be used on paraffin-embedded tissue samples to confirm the presence of Myxoma virus and identify the viral strain. At present, no specific treatment exists for myxomatosis. If the decision is made to attempt treatment, careful monitoring is necessary to avoid prolonging suffering. Previously vaccinated rabbits or those infected with an attenuated strain may recover given supportive care with fluids, food, and broad spectrum antivirals. Cessation of food and water intake, ongoing severe weight loss, or rectal temperatures below 37 °C (98.6 °F) are reasons to consider euthanasia. Vaccines against myxomatosis are available in some countries. All are modified live vaccines based either on attenuated myxoma virus strains or on the closely related Shope fibroma virus , which provides cross-immunity. It is recommended that all rabbits in areas of the world where myxomatosis is endemic be routinely vaccinated, even if kept indoors, because of the ability of the virus to be carried inside by vectors or fomites . In group situations where rabbits are not routinely vaccinated, vaccination in the face of an outbreak is beneficial in limiting morbidity and mortality. The vaccine does not provide 100% protection, so it is still important to prevent contact with wild rabbits and insect vectors. Myxomatosis vaccines must be boostered regularly to remain effective, and annual vaccinations are usually recommended. In Europe and the United Kingdom a bivalent vectored vaccine called Nobivac Myxo-RHD is available that protects against both myxomatosis and rabbit haemorrhagic disease . This vaccine is licensed for immunization of rabbits 5 weeks of age or older, with onset of immunity taking approximately 3 weeks. Protection against myxomatosis and rabbit hemorrhagic disease has a duration of immunity for 12 months, and annual vaccination is recommended to ensure continued protection. The vaccine has been shown to reduce mortality and clinical signs of myxomatosis. Vaccination against myxomatosis is currently prohibited in Australia due to concerns that the vaccine virus could spread to wild rabbits and increase their immunity to myxomatosis. As feral rabbits in Australia already cause a great deal of environmental damage, this concern is taken seriously by the government. Many pet rabbits in Australia continue to die from myxomatosis due to their lack of immunity. There is at least one campaign to allow the vaccine for domestic pets. The Australian Veterinary Association supports the introduction of a safe and effective myxomatosis vaccine for pet rabbits, and the RSPCA of Australia has repeatedly called for a review of available myxoma virus vaccines and a scientific assessment of their likely impacts in the Australian setting. Although myxomatosis is endemic in parts of Mexico and the United States, there is no commercially available vaccine in either of these countries. Information on recently reported cases in the United States is available from the House Rabbit Society. In the United States the importation of vaccines is overseen by the Animal and Plant Health Inspection Service, part of the Department of Agriculture. In locations where myxomatosis is endemic but no vaccine is available, preventing exposure to the myxoma virus is of vital importance. Even vaccinated rabbits need protection, as the vaccines are not 100% effective. The risk of a pet contracting myxomatosis can be reduced by preventing contact with wild rabbits, keeping rabbits indoors (preferred) or behind screens to prevent mosquito exposure, and using rabbit-safe medications to treat and prevent fleas, lice, and mites. Any new rabbit that may have been exposed should be quarantined, and rabbits suspected of having myxomatosis should be immediately isolated until the diagnosis is ruled out. If the disease is confirmed all contaminated cages, dishes, or other objects should be disinfected with 10% bleach, 10% sodium hydroxide, or 1%–1.4% formalin. Vaccines against myxomatosis are available in some countries. All are modified live vaccines based either on attenuated myxoma virus strains or on the closely related Shope fibroma virus , which provides cross-immunity. It is recommended that all rabbits in areas of the world where myxomatosis is endemic be routinely vaccinated, even if kept indoors, because of the ability of the virus to be carried inside by vectors or fomites . In group situations where rabbits are not routinely vaccinated, vaccination in the face of an outbreak is beneficial in limiting morbidity and mortality. The vaccine does not provide 100% protection, so it is still important to prevent contact with wild rabbits and insect vectors. Myxomatosis vaccines must be boostered regularly to remain effective, and annual vaccinations are usually recommended. In Europe and the United Kingdom a bivalent vectored vaccine called Nobivac Myxo-RHD is available that protects against both myxomatosis and rabbit haemorrhagic disease . This vaccine is licensed for immunization of rabbits 5 weeks of age or older, with onset of immunity taking approximately 3 weeks. Protection against myxomatosis and rabbit hemorrhagic disease has a duration of immunity for 12 months, and annual vaccination is recommended to ensure continued protection. The vaccine has been shown to reduce mortality and clinical signs of myxomatosis. Vaccination against myxomatosis is currently prohibited in Australia due to concerns that the vaccine virus could spread to wild rabbits and increase their immunity to myxomatosis. As feral rabbits in Australia already cause a great deal of environmental damage, this concern is taken seriously by the government. Many pet rabbits in Australia continue to die from myxomatosis due to their lack of immunity. There is at least one campaign to allow the vaccine for domestic pets. The Australian Veterinary Association supports the introduction of a safe and effective myxomatosis vaccine for pet rabbits, and the RSPCA of Australia has repeatedly called for a review of available myxoma virus vaccines and a scientific assessment of their likely impacts in the Australian setting. Although myxomatosis is endemic in parts of Mexico and the United States, there is no commercially available vaccine in either of these countries. Information on recently reported cases in the United States is available from the House Rabbit Society. In the United States the importation of vaccines is overseen by the Animal and Plant Health Inspection Service, part of the Department of Agriculture. In locations where myxomatosis is endemic but no vaccine is available, preventing exposure to the myxoma virus is of vital importance. Even vaccinated rabbits need protection, as the vaccines are not 100% effective. The risk of a pet contracting myxomatosis can be reduced by preventing contact with wild rabbits, keeping rabbits indoors (preferred) or behind screens to prevent mosquito exposure, and using rabbit-safe medications to treat and prevent fleas, lice, and mites. Any new rabbit that may have been exposed should be quarantined, and rabbits suspected of having myxomatosis should be immediately isolated until the diagnosis is ruled out. If the disease is confirmed all contaminated cages, dishes, or other objects should be disinfected with 10% bleach, 10% sodium hydroxide, or 1%–1.4% formalin. Myxoma virus was the first virus intentionally introduced into the wild with the purpose of eradicating a vertebrate pest, namely the European rabbit in Australia and Europe. The long-term failure of this strategy has been due to natural selective pressures on both the rabbit and virus populations, which resulted in the emergence of myxomatosis-resistant animals and attenuated virus variants. The process is regarded as a classical example of host–pathogen coevolution following cross-species transmission of a pathogen. European rabbits were brought to Australia in 1788 by early English settlers. Initially used as a food source, they later became feral and their numbers soared. In November 1937, the Australian Council for Scientific and Industrial Research used Wardang Island to conduct its first field trials of myxomatosis, which established the methodology for the successful release of the myxoma virus throughout the country. In 1950, the SLS strain of myxoma virus from the South American tapeti ( Sylvilagus brasiliensis ) was released in Australia as a biological control agent against feral rabbits. The virus was at first highly lethal, with an estimated case fatality rate of close to 99.8%. Within a few years, however, this strain was replaced by less virulent ones, which permitted longer survival of infected rabbits and enhanced disease transmission. The virus created strong selection pressure for the evolution of rabbits resistant to myxomatosis. As rabbits became more resistant the viral strains responded by becoming less virulent. Rabbit hemorrhagic disease virus has also been used to control wild rabbit populations in Australia since 1995. In June 1952, Paul-Félix Armand-Delille , the owner of an estate in northwestern France, inoculated two wild rabbits with the Lausanne strain of myxoma virus. His intention was to only eradicate rabbits on his property and town, but the disease quickly spread through Western Europe, Ireland and the United Kingdom. Some dissemination of the virus clearly appeared deliberate, such as the introduction into Britain in 1953 and the introduction into Ireland in 1954. Unlike in Australia, however, strenuous efforts were made to stop the spread in Europe. These efforts proved in vain. According to estimates, the wild rabbit population in the United Kingdom fell by 99%, in France by 90% to 95%, and in Spain by 95%. This in turn drove specialized rabbit predators, such as the Iberian lynx and the Spanish imperial eagle , to the brink of extinction. Myxomatosis not only decreased the wild rabbit population and the population of its natural predators, but also had significant impacts on the large rabbit-farming industry, which produced domestic rabbits for meat and fur. The Lausanne strain of the myxoma virus causes the formation of large purple skin-nodules, a sign not seen in other strains. As happened in Australia, the virus has generally become less virulent and the wild rabbit populations more resistant subsequently. The introduction of myxomatosis into New Zealand in 1952 to control a burgeoning rabbit problem failed for lack of a vector. Two pairs of European rabbits set free in 1936 at Punta Santa Maria resulted in an infestation that spread over the northern half of Tierra del Fuego . More rabbits were introduced in 1950 near Ushuaia by the Argentinian Navy and a private rabbit farmer. The rabbits quickly became pests, riddling the ground with holes and leaving it bare of grass. By 1953 the rabbit population numbered about 30 million. In 1954 Chilean authorities introduced a Brazilian strain of myxoma virus to Tierra del Fuego, which succeeded in bringing rabbits to very low population levels. European rabbits were brought to Australia in 1788 by early English settlers. Initially used as a food source, they later became feral and their numbers soared. In November 1937, the Australian Council for Scientific and Industrial Research used Wardang Island to conduct its first field trials of myxomatosis, which established the methodology for the successful release of the myxoma virus throughout the country. In 1950, the SLS strain of myxoma virus from the South American tapeti ( Sylvilagus brasiliensis ) was released in Australia as a biological control agent against feral rabbits. The virus was at first highly lethal, with an estimated case fatality rate of close to 99.8%. Within a few years, however, this strain was replaced by less virulent ones, which permitted longer survival of infected rabbits and enhanced disease transmission. The virus created strong selection pressure for the evolution of rabbits resistant to myxomatosis. As rabbits became more resistant the viral strains responded by becoming less virulent. Rabbit hemorrhagic disease virus has also been used to control wild rabbit populations in Australia since 1995. In June 1952, Paul-Félix Armand-Delille , the owner of an estate in northwestern France, inoculated two wild rabbits with the Lausanne strain of myxoma virus. His intention was to only eradicate rabbits on his property and town, but the disease quickly spread through Western Europe, Ireland and the United Kingdom. Some dissemination of the virus clearly appeared deliberate, such as the introduction into Britain in 1953 and the introduction into Ireland in 1954. Unlike in Australia, however, strenuous efforts were made to stop the spread in Europe. These efforts proved in vain. According to estimates, the wild rabbit population in the United Kingdom fell by 99%, in France by 90% to 95%, and in Spain by 95%. This in turn drove specialized rabbit predators, such as the Iberian lynx and the Spanish imperial eagle , to the brink of extinction. Myxomatosis not only decreased the wild rabbit population and the population of its natural predators, but also had significant impacts on the large rabbit-farming industry, which produced domestic rabbits for meat and fur. The Lausanne strain of the myxoma virus causes the formation of large purple skin-nodules, a sign not seen in other strains. As happened in Australia, the virus has generally become less virulent and the wild rabbit populations more resistant subsequently. The introduction of myxomatosis into New Zealand in 1952 to control a burgeoning rabbit problem failed for lack of a vector. Two pairs of European rabbits set free in 1936 at Punta Santa Maria resulted in an infestation that spread over the northern half of Tierra del Fuego . More rabbits were introduced in 1950 near Ushuaia by the Argentinian Navy and a private rabbit farmer. The rabbits quickly became pests, riddling the ground with holes and leaving it bare of grass. By 1953 the rabbit population numbered about 30 million. In 1954 Chilean authorities introduced a Brazilian strain of myxoma virus to Tierra del Fuego, which succeeded in bringing rabbits to very low population levels. Given the importance of viral evolution to disease emergence, pathogenesis , drug resistance, and vaccine efficacy, it has been well studied by theoreticians and experimentalists. The introductions of myxoma virus into European rabbit populations in Australia and France created natural experiments in virulence evolution. While initial viral strains were highly virulent, attenuated strains were soon recovered from the field. These attenuated strains, which allowed rabbits to survive longer, came to dominate because they were more readily transmitted. As the complete genome sequences of multiple myxoma strains have been published, scientists have been able to pinpoint exactly which genes are responsible for the changes in the myxoma virus's virulence and behavior. However, the evolution of the disease has proved to be increasingly complex and unpredictable, both among various strains of host, and among strains of the virus. Both in modes of resistance and of virulence, and in all countries in which the virus has been introduced for control of feral rabbits, the hosts and the pathogens have continually adapted in various ways to evolutionary challenges. Although current strains of myxomatosis do not provide sufficient control on their own, the disease remains a significant ecological factor in rabbit control, both in Australia and in other countries. For example, in spite of long-term concern in Australia especially, where the initial virulence of myxomatosis declined after a few decades in the field, rabbit evolution of resistance to the disease has not gone unchallenged. For some recent strains of the virus, as a case in point, selection for reduced inflammation prolongs virus replication, which enhances transmission and reduces suppression of the virus by the host's fever; it also may cause immunosuppression, which favours high virulence. Studies continue, both in the contexts of rabbit control, and of the relevant evolutionary principles.Myxomatosis is referred to as "the white blindness" by the rabbit characters of the novel Watership Down (1972) by Richard Adams , and in the story a rabbit chief had driven out all rabbits who seemed to be afflicted. In one of the novel's folk tales about the rabbit hero El-ahrairah, the transmission of the disease is explained to him by the lord of the rabbit underworld, the Black Rabbit of Inle ("it is carried by the fleas in rabbits' ears; they pass from the ears of a sick rabbit to those of his companions"). The sixth album of British band Radiohead , Hail to the Thief , contains a song "Myxomatosis". The disease is used as analogy to the journalist attention the band has. Thom Yorke has said: "I remember my parents pointing out all these dead rabbits on the road when I was a kid. I didn't know that much about the virus, or even how to spell it, but I loved the word. I loved the way it sounded."

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Crimean-Congo haemorrhagic fever

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Venezuelan equine encephalitis virus

Venezuelan equine encephalitis virus is a mosquito -borne viral pathogen that causes Venezuelan equine encephalitis or encephalomyelitis ( VEE ). VEE can affect all equine species, such as horses , donkeys , and zebras . After infection, equines may suddenly die or show progressive central nervous system disorders. Humans also can contract this disease. Healthy adults who become infected by the virus may experience flu -like symptoms, such as high fevers and headaches. People with weakened immune systems and the young and the elderly can become severely ill or die from this disease. The virus that causes VEE is transmitted primarily by mosquitoes that bite an infected animal and then bite and feed on another animal or human. The speed with which the disease spreads depends on the subtype of the VEE virus and the density of mosquito populations. Enzootic subtypes of VEE are diseases endemic to certain areas. Generally these serotypes do not spread to other localities. Enzootic subtypes are associated with the rodent-mosquito transmission cycle. These forms of the virus can cause human illness but generally do not affect equine health. Epizootic subtypes, on the other hand, can spread rapidly through large populations. These forms of the virus are highly pathogenic to equines and can also affect human health. Equines, rather than rodents, are the primary animal species that carry and spread the disease. Infected equines develop an enormous quantity of virus in their circulatory system. When a blood-feeding insect feeds on such animals, it picks up this virus and transmits it to other animals or humans. Although other animals, such as cattle, swine, and dogs, can become infected, they generally do not show signs of the disease or contribute to its spread. The virion is spherical and approximately 70 nm in diameter. It has a lipid membrane with glycoprotein surface proteins spread around the outside. Surrounding the nuclear material is a nucleocapsid that has an icosahedral symmetry of T = 4, and is approximately 40 nm in diameter.Serology testing performed on this virus has shown the presence of six different subtypes (classified I to VI). These have been given names, including Mucambo, Tonate, and Pixuna subtypes. There are seven different variants in subtype I, and three of these variants, A, B, and C are the epizootic strains. [ citation needed ] The Mucambo virus (subtype III) appears to have evolved ~1807 AD (95% credible interval: 1559–1944). In Venezuela the Mucambo subtype was identified in 1975 by Jose Esparza and J. Sánchez using cultured mosquito cells. In the Americas, there have been 21 reported outbreaks of Venezuelan equine encephalitis virus. Outbreaks occurred in Central American and South American countries. This virus was isolated in 1938, and outbreaks have been reported in many different countries since then. Mexico, Colombia, Venezuela, and the United States are just some of the countries that have reported outbreaks. Outbreaks of VEE generally occur after periods of heavy precipitation that cause mosquito populations to thrive. Between December 1992 and January 1993, the Venezuelan state of Trujillo experienced an outbreak of this virus. Overall, 28 cases of the disease were reported along with 12 deaths. June 1993 saw a bigger outbreak in the Venezuelan state of Zulia , as 55 humans died as well as 66 equine deaths. A much larger outbreak in Venezuela and Colombia occurred in 1995. On May 23, 1995, equine encephalitis -like cases were reported in the northwest portion of the country. Eventually, the outbreak spread more towards the north as well as to the south. The outbreak caused about 11,390 febrile cases in humans as well as 16 deaths. About 500 equine cases were reported with 475 deaths. An outbreak of this disease occurred in Colombia on September 1995. This outbreak resulted in 14,156 human cases that were attributable to Venezuelan equine encephalitis virus with 26 human deaths. A possible explanation for the serious outbreaks was the particularly heavy rain that had fallen. This could have caused increased numbers of mosquitoes that could serve as vectors for the disease. A more likely explanation is that deforestation caused a change in mosquito species. Culex taenopius mosquitos, which prefer rodents, were replaced by Aedes taeniorhynchus mosquitoes, which are more likely to bite humans and large equines. [ citation needed ] Though the majority of VEE outbreaks occur in Central and South America, the virus has potential to outbreak again in the United States. It has been shown the invasive mosquito species Aedes albopictus is a viable carrier of VEEV. There is an inactivated vaccine containing the C-84 strain for VEEV that is used to immunize horses. Another vaccine, containing the TC-83 strain, is only used on humans in military and laboratory positions that risk contracting the virus. The human vaccine can result in side effects and does not fully immunize the patient. The TC-83 strain was generated by passing the virus 83 times through a guinea pig heart cell culture ; C-84 is a derivative of TC-83. In April 2009, the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick reported that samples of Venezuelan equine encephalitis virus were discovered missing during an inventory of a group of samples left by a departed researcher. The report stated the samples were likely among those destroyed when a freezer malfunctioned. During the Cold War , both the United States biological weapons program and the Soviet biological weapons program researched and weaponized VEE. In his book Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World , author Stephen Handelman details the weaponization of VEE and other biologicals including plague, anthrax, and smallpox, by Dr. Ken Alibek in the Cold War Soviet weapons programs. [ citation needed ]During the Cold War , both the United States biological weapons program and the Soviet biological weapons program researched and weaponized VEE. In his book Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World , author Stephen Handelman details the weaponization of VEE and other biologicals including plague, anthrax, and smallpox, by Dr. Ken Alibek in the Cold War Soviet weapons programs. [ citation needed ]

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Crimean-Congo haemorrhagic fever

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National Institute of Virology

The National Institute of Virology in Pune , India is an Indian virology research institute and part of the Indian Council of Medical Research (ICMR). It was previously known as 'Virus Research Centre' and was founded in collaboration with the Rockefeller Foundation . It has been designated as a WHO H5 reference laboratory for SE Asia region. The Virus Research Centre (VRC), Pune came into existence in 1952 under the joint auspices of the ICMR and the Rockefeller Foundation , as a part of the global programme of investigations on the arthropod -borne group of viruses . In view of its expanded scope and activities, the VRC was re-designated as the National Institute of Virology (NIV) in 1978. The NIV is identified today as the WHO Collaborating Centres for arboviruses reference and hemorrhagic fever reference and research. NIV is also the National Monitoring Centre for Influenza , Japanese encephalitis , Rota , Measles , Hepatitis and Coronavirus . The National Institute of Virology is one of the major Institutes of the Indian Council of Medical Research (ICMR). It was established at Pune , Maharashtra , India in 1952 as Virus Research Centre (VRC) under the auspices of the ICMR and the Rockefeller Foundation (RF), USA. It was an outcome of the global programme of the RF for investigating the Arthropod Borne viruses. Since the studies on arboviruses and their arthropod vectors involve most of the basic principles and techniques of general virology , entomology and zoology , these viruses were also considered to be an ideal group, to begin with, for intensive training and research in virology . The RF withdrew its support in 1967 and since then the institute has been funded by the ICMR . The institute was designated as one of the collaborating laboratories of the World Health Organization (WHO) in 1967 and it started functioning as the regional centre of the WHO for South-East Asia for arbovirus studies from 1969. Since 1974, it has been functioning as a WHO collaborating centre for arbovirus reference and research. In 1995 it has been redesignated as the WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research and Rapid Diagnosis of Viral Diseases. NIV is also the National Centre for Hepatitis and Influenza .It has outstations in Bangalore, Kerala and Mumbai. The field unit of NIV at Bengaluru is one of the centres under National Polio Surveillance Programme conducting surveillance of acute flaccid paralysis cases from Karnataka as a part of Global Polio Eradication Programme of the WHO South-East Asia region since 1997. World Health Organization (WHO) Regional Collaborating Centre for Reference and Research on Arboviruses , Influenza and Measles as well as National Reference Centre for Hepatitis , Avian Influenza and emerging infectious diseases . The institute conducts an M.Sc. in Virology and a PhD course, under the aegis of the Savitribai Phule Pune University , Pune. Research areas include Cell repository, Electron microscopy, Rickettsioses , Hepatitis , Influenza and related viruses, Clinical virology, Biochemistry , Virus registry, and Biostatistics . The research activities of the Institute are coordinated by a Scientific Advisory Committee (SAC). [ citation needed ]On the recommendation of the SAC, the VRC acquired its status of national importance and was renamed as the National Institute of Virology (NIV) in 1978. Subsequently, studies on Acquired Immune Deficiency Syndrome (AIDS), Rotavirus gastroenteritis , acute haemorrhagic conjunctivitis , Rabies , Herpes simplex, Buffalo pox , Measles , and Poliomyelitis were also initiated. A Microbial Containment Complex (MCC) having P-3 biosafety levels for handling microorganisms of highly infectious nature is being established at Pashan, 11 km off the main laboratory at Pune . The laboratory will provide a National Containment facility for the safe handling of hazardous pathogens . Landmark achievements Thrust Areas in viral diseases of public health importance

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Crimean-Congo haemorrhagic fever

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Arbovirus

Arbovirus is an informal name for any virus that is transmitted by arthropod vectors . The term arbovirus is a portmanteau word ( ar thropod- bo rne virus ). Tibovirus ( ti ck- bo rne virus ) is sometimes used to more specifically describe viruses transmitted by ticks , a superorder within the arthropods. Arboviruses can affect both animals (including humans) and plants. In humans, symptoms of arbovirus infection generally occur 3–15 days after exposure to the virus and last three or four days. The most common clinical features of infection are fever , headache , and malaise , but encephalitis and viral hemorrhagic fever may also occur. The incubation period – the time between when infection occurs and when symptoms appear – varies from virus to virus, but is usually limited between 2 and 15 days for arboviruses. The majority of infections, however, are asymptomatic. Among cases in which symptoms do appear, symptoms tend to be non-specific, resembling a flu-like illness , and are not indicative of a specific causative agent. These symptoms include fever, headache, malaise, rash and fatigue. Rarely, vomiting and hemorrhagic fever may occur. The central nervous system can also be affected by infection, as encephalitis and meningitis are sometimes observed. Prognosis is good for most people, but is poor in those who develop severe symptoms, with up to a 20% mortality rate in this population depending on the virus. The very young, elderly, pregnant women, and people with immune deficiencies are more likely to develop severe symptoms. [ citation needed ]Arboviruses maintain themselves in nature by going through a cycle between a host , an organism that carries the virus, and a vector , an organism that carries and transmits the virus to other organisms. For arboviruses, vectors are commonly mosquitoes, ticks, sandflies and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes. Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts. Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the host's blood. While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia , a condition in which there are large numbers of virions present in the blood. The abundance of virions in the host's blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector. An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of passerine birds, making them the hosts of the virus. When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals , humans are considered a dead-end host. Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions , organ transplantation , and the use of blood products can transmit arboviruses if the virus is present in the donor's blood or organs. Because of this, blood and organs are often screened for viruses before being administered. Rarely, vertical transmission , or mother-to-child transmission, has been observed in infected pregnant and breastfeeding women. Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal. This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations. Arboviruses are a polyphyletic group , belonging to various viral genera and therefore exhibiting different virologic characteristics.Arboviruses maintain themselves in nature by going through a cycle between a host , an organism that carries the virus, and a vector , an organism that carries and transmits the virus to other organisms. For arboviruses, vectors are commonly mosquitoes, ticks, sandflies and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes. Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts. Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the host's blood. While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia , a condition in which there are large numbers of virions present in the blood. The abundance of virions in the host's blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector. An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of passerine birds, making them the hosts of the virus. When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals , humans are considered a dead-end host. Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions , organ transplantation , and the use of blood products can transmit arboviruses if the virus is present in the donor's blood or organs. Because of this, blood and organs are often screened for viruses before being administered. Rarely, vertical transmission , or mother-to-child transmission, has been observed in infected pregnant and breastfeeding women. Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal. This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations. Arboviruses are a polyphyletic group , belonging to various viral genera and therefore exhibiting different virologic characteristics.Preliminary diagnosis of arbovirus infection is usually based on clinical presentations of symptoms, places and dates of travel, activities, and epidemiological history of the location where infection occurred. Definitive diagnosis is typically made in a laboratory by employing some combination of blood tests , particularly immunologic , serologic and/or virologic techniques such as ELISA , complement fixation , polymerase chain reaction , neutralization test , and hemagglutination-inhibition test . In the past, arboviruses were organized into one of four groups: A, B, C, and D. Group A denoted members of the genus Alphavirus , Group B were members of the genus Flavivirus , and Group C remains as the Group C serogroup of the genus Orthobunyavirus . Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus . Currently, viruses are jointly classified according to Baltimore classification and a virus-specific system based on standard biological classification . With the exception of the African swine fever virus , which belongs to the Asfarviridae family of viruses, all major clinically important arboviruses belong to one of the following four groups: [ citation needed ]In the past, arboviruses were organized into one of four groups: A, B, C, and D. Group A denoted members of the genus Alphavirus , Group B were members of the genus Flavivirus , and Group C remains as the Group C serogroup of the genus Orthobunyavirus . Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus . Currently, viruses are jointly classified according to Baltimore classification and a virus-specific system based on standard biological classification . With the exception of the African swine fever virus , which belongs to the Asfarviridae family of viruses, all major clinically important arboviruses belong to one of the following four groups: [ citation needed ]Vector control measures, especially mosquito control , are essential to reducing the transmission of disease by arboviruses. Habitat control involves draining swamps and removal of other pools of stagnant water (such as old tires, large outdoor potted plants, empty cans, etc.) that often serve as breeding grounds for mosquitoes. Insecticides can be applied in rural and urban areas, inside houses and other buildings, or in outdoor environments. They are often quite effective for controlling arthropod populations, though use of some of these chemicals is controversial, and some organophosphates and organochlorides (such as DDT ) have been banned in many countries. Infertile male mosquitoes have been introduced in some areas in order to reduce the breeding rate of relevant mosquito species. Larvicides are also used worldwide in mosquito abatement programs. Temefos is a common mosquito larvicide. People can also reduce the risk of getting bitten by arthropods by employing personal protective measures such as sleeping under mosquito nets , wearing protective clothing , applying insect repellents such as permethrin and DEET to clothing and exposed skin, and (where possible) avoiding areas known to harbor high arthropod populations. Arboviral encephalitis can be prevented in two major ways: personal protective measures and public health measures to reduce the population of infected mosquitoes. Personal measures include reducing time outdoors particularly in early evening hours, wearing long pants and long sleeved shirts and applying mosquito repellent to exposed skin areas. Public health measures often require spraying of insecticides to kill juvenile (larvae) and adult mosquitoes. Vaccines are available for the following arboviral diseases: Vaccines are in development for the following arboviral diseases:Vaccines are available for the following arboviral diseases: Vaccines are in development for the following arboviral diseases:Because the arboviral encephalitides are viral diseases, antibiotics are not an effective form of treatment and no effective antiviral drugs have yet been discovered. Treatment is supportive, attempting to deal with problems such as swelling of the brain, loss of the automatic breathing activity of the brain and other treatable complications like bacterial pneumonia . The WHO caution against the use of aspirin and ibuprofen as they can increase the risk of bleeding. Most arboviruses are located in tropical areas, however as a group they have a global distribution. The warm climate conditions found in tropical areas allows for year-round transmission by the arthropod vectors. Other important factors determining geographic distribution of arthropod vectors include rainfall, humidity, and vegetation. Mapping methods such as GIS and GPS have allowed for spatial and temporal analyses of arboviruses. Tagging cases or breeding sites geographically has allowed for deeper examination of vector transmission. To see the epidemiology of specific arboviruses, the following resources hold maps, fact sheets, and reports on arboviruses and arboviral epidemics. The WHO also hosts DengueNet, a database which can be queried about Dengue cases. Arboviruses were not known to exist until the rise of modern medicine , with the germ theory and an understanding that viruses were distinct from other microorganisms . The connection between arthropods and disease was not postulated until 1881 when Cuban doctor and scientist Carlos Finlay proposed that yellow fever may be transmitted by mosquitoes instead of human contact, a reality that was verified by Major Walter Reed in 1901. The primary vector, Aedes aegypti , had spread globally from the 15th to the 19th centuries as a result of globalization and the slave trade . This geographic spreading caused dengue fever epidemics throughout the 18th and 19th centuries, and later, in 1906, transmission by the Aedes mosquitoes was confirmed, making yellow fever and dengue fever the first two diseases known to be caused by viruses. Thomas Milton Rivers published the first clear description of a virus as distinct from a bacterium in 1927. The discovery of the West Nile virus came in 1937, and has since been found in Culex populations causing epidemics throughout Africa , the Middle East , and Europe . The virus was introduced into the Western Hemisphere in 1999, sparking a series of epidemics. During the latter half of the 20th century, Dengue fever reemerged as a global disease, with the virus spreading geographically due to urbanization , population growth , increased international travel, and global warming , and continues to cause at least 50 million infections per year, making Dengue fever the most common and clinically important arboviral disease. Yellow fever , alongside malaria , was a major obstacle in the construction of the Panama Canal . French supervision of the project in the 1880s was unsuccessful because of these diseases, forcing the abandonment of the project in 1889. During the American effort to construct the canal in the early 1900s, William C. Gorgas , the Chief Sanitary Officer of Havana , was tasked with overseeing the health of the workers. He had past success in eradicating the disease in Florida and Havana by reducing mosquito populations through draining nearby pools of water, cutting grass, applying oil to the edges of ponds and swamps to kill larvae , and capturing adult mosquitoes that remained indoors during the daytime. Joseph Augustin LePrince , the Chief Sanitary Inspector of the Canal Zone , invented the first commercial larvicide , a mixture of carbolic acid , resin , and caustic soda , to be used throughout the Canal Zone . The combined implementation of these sanitation measures led to a dramatic decline in the number of workers dying and the eventual eradication of yellow fever in the Canal Zone as well as the containment of malaria during the 10-year construction period. Because of the success of these methods at preventing disease, they were adopted and improved upon in other regions of the world.

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Crimean-Congo haemorrhagic fever

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Kemerovo tickborne viral fever

Kemerovo tickborne viral fever is an aparalytic febrile illness accompanied by meningism following tick-bite. The causative agent is a zoonotic Orbivirus first described in 1963 in western Siberia by Mikhail Chumakov and coworkers. The virus has some 23 serotypes , and can occur in coinfections with other Orbiviruses and tick-transmitted encephalitis viruses, complicating the course of illness. Rodents and birds are the primary vertebrate hosts of the virus; Ixodes persulcatus ticks are a vector of the virus. Kemerovo and related viruses may be translocated distances in the environment by migratory birds .

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Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/One_Health_Model/html

One Health Model

The concept of One Health is the unity of multiple practices that work together locally, nationally, and globally to help achieve optimal health for people, animals, and the environment. When the people, animals, and environment are put together they make up the One Health Triad . The One Health Triad shows how the health of people, animals, and the environment is linked to one another. With One Health being a worldwide concept, it makes it easier to advance health care in the 21st century. When this concept is used, and applied properly, it can help protect people, animals, and the environment in the present and future generations. The origins of the One Health Model dates as far back as 1821, with the first links between human and animal diseases being recognized by Rudolf Virchow . Virchow noticed links between human and animal disease, coining the term " zoonosis ." The major connection Virchow made was between Trichinella spiralis in swine and human infections. It was over a century later before the ideas laid out by Virchow were integrated into a single health model connecting human health with animal health. In 1964, Dr. Calvin Schwabe, a former member of World Health Organization (WHO) and the founding chair of Department of Epidemiology and Preventive Medicine at the Veterinary School at the University of California Davis, called for a "One Medicine" model emphasizing the need for collaboration between human and wildlife pathologists as a means of controlling and even preventing disease spread. It would be another four decades before the One Health became a reality with the 12 Manhattan Principles, where human and animal pathologists called for "One Health, One World." The One Health Model has gained momentum in recent years due to the discovery of the multiple interconnections that exist between animal and human disease. Recent estimates place zoonotic diseases as the source 60% of total human pathogens, and 75% of emerging human pathogens. The One Health Model can constantly be applied with human and animal interactions. One of the main situations where One Health can be applied is with canine and feline obesity being linked to their owners and their own obesity. Obesity in canines and felines is not good for them nor is it good for humans. The obesity of humans and their animals can result in many health problems such as diabetes mellitus, osteoarthritis, and many others. In some cases if the obesity of the pet is too bad the pet may be removed from its owner and put up for adoption. The only solution for this issue is to encourage owners to have a healthy lifestyle for both them and their animals. Zoonotic Diseases is another situation that the One Health model can be applied to. This is talked about more in the Zoonotic Disease section.Antibiotic resistance is becoming a serious problem in today's agriculture industry and for humans. One reason for this occurring resistance is that natural resistomes are present in different environmental niches. These environmental resistomes function as an antibiotic resistance gene. There are many questions and research that needs to be further done to find out if these environmental resistomes play a big role in the antibiotic resistance that is occurring in humans, animals, and plants. A recent study was done and reported that 700 000 annual deaths were caused by infections due to drug resistant pathogens This study also reported that if unchecked, this number will increase to 10 million by 2050. The National Antimicrobial Monitoring System is a system used to monitor antimicrobial resistance among bacteria that is isolated from animals that are used as food In 2013, they found that about 29% of turkeys, 18% of swine, 17% of beef, and 9% of chicken were multi drug resistant, meaning they had resistance to 3 or more classes of antimicrobials. Having this resistance for both animals and humans makes it easier for zoonotic diseases to be transferred between them and also makes it easier for the resistance of these antimicrobials to be passed on. With this being said, there are many possible risk management options that can be taken to help reduce this possibility. Most of these risk management options can take place on the farm or at the slaughter house for animals. When it comes to humans, risk management has to be done by you yourself and you have to be responsible for good hygiene, up to date vaccinations, and proper use of antibiotics. With that being said, the same management on farms needs to be taken for proper use of antibiotics and only using them when it is absolutely necessary and improving the general hygiene in all stages of production. With these management factors added in with research and knowledge on the amount of resistance within our environment, antimicrobial resistance may be able to be controlled and help reduce the amount of zoonotic diseases that are passed between animals and humans. Zoonosis or zoonotic disease can be defined as an infectious disease that can be transmitted between animals and humans. One Health plays a big role in helping to prevent and control zoonotic diseases. Approximately 75% of new and emerging infectious diseases in humans are defined as zoonotic. Zoonotic diseases can be spread in many different ways. The most common known ways they are spread are through direct contact, indirect contact, vector-borne, and food-borne. Below in (Table 1) you can see a list of different zoonotic diseases, their main reservoirs, and their mode of transmission. Table 1: Zoonotic Diseases

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Crimean-Congo haemorrhagic fever

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List of notifiable diseases

The following is a list of notifiable diseases arranged by country.

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Crimean-Congo haemorrhagic fever

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Bernhard Nocht Institute for Tropical Medicine

Bernhard Nocht Institute for Tropical Medicine (Bernhard-Nocht-Institut für Tropenmedizin) (BNITM) in Hamburg is Germany 's largest institution for tropical medicine , with a workforce of about 250 people in Hamburg. It is member of the Leibniz-Association .The cholera epidemic of the year 1892 claimed thousands of lives and prompted the Senate and Parliament of the City of Hamburg to reform the health care system. The Tropical Medicine Institute was founded with the support of the Imperial Government to research ship and tropical diseases and to train ship and colonial physicians. In 1893, the naval physician Bernhard Nocht [ de ] was introduced to the newly created position of port physician. For the medical care of seamen suffering from internal diseases, he was also given a department in the St. Georg General Hospital. Contrary to the plans of the bacteriologist Robert Koch , Nocht established Hamburg in 1899 as the location for an institute for the research of tropical diseases, since "due to overseas traffic there are many people with treatment needs at this point". On 1 October 1900 the "Institute for Maritime and Tropical Diseases" with 24 employees was opened in the former administration building of the naval hospital at Hamburg's Landungsbrücken. Since 2006, the inpatient care has taken place at the University Medical Center Hamburg-Eppendorf .Between 1910 and 1914, the three-part clinker building with laboratory wing, hospital and animal house was built according to plans by Fritz Schumacher . The building wing is located in the St. Pauli district between Bernhard Nocht Street on the high north side and the slope of Davidstreet [ de ] leading down to the harbor shore. After 1945 the building, damaged by bombs, was re-built. From 2003 a new wing was built on the site of the former animal house, which was put into operation at the end of January 2008. In particular, the high-security laboratories were completely redesigned and have since then been among the safest in the world ( biosafety level 4 ). The numerous decorative reliefs on the façade of the old building were created by the artist Johann Michael Bossard [ de ] . The buildings of the Regional Centre of the German Weather Service and the Federal Maritime and Hydrographic Agency are located in the course of the road to the east.The institute is divided into three research sections: the Molecular Biology and Immunology Division, the Clinical Research Division and the Epidemiology and Diagnostics Division. The National Reference Centre for Tropical Pathogens is also located at BNITM. Until the end of 2007, the Bernhard Nocht Institute was supported by the Federal Ministry of Health and the Ministry of Social Affairs, Family, Health and Consumer Protection of the Free and Hanseatic City of Hamburg. On 1 January 2008, the BNITM merged into the Leibniz Association . The Institute's current scientific focus is on malaria , haemorrhagic fever viruses ( Lassa , Marburg , Ebola and Crimean Congo Virus), on immunology, epidemiology and clinical studies of tropical infections as well as on the mechanisms of the viral transmission by mosquitoes. For the handling of highly pathogenic viruses and infected insects, the Institute has laboratories of the highest biosafety level ( BSL-4 ) and a BSL-3 insectary. The BNITM comprises the National Reference Centre for the detection of all tropical pathogens and the WHO Collaborating Centre for arboviruses and haemorrhagic fever viruses. Recent successes of the institute include the identification and development of a test for the SARS pathogen ( Christian Drosten , Stephan Günther [ de ] 2003), the development of new therapeutic approaches against nematodes, especially in river blindness (Achim Hörauf 1998), on bacteria living symbiotically with the worms, and the clarification of a still missing transitional stage of the malaria pathogen (Merosome, Volker Heussler [ de ] 2006). The couple Paul Racz [ de ] and Klara Tenner-Racz from the Institute's Pathology Department is also known for their achievements in AIDS research. The following list contains a few of the contributions made at the Bernhard Nocht Institute: The following list contains a few of the contributions made at the Bernhard Nocht Institute: Since 2008, the institute has been headed by a board of trustees. It consists of three scientists and the commercial director. The first chairman of the board was the physician Rolf Horstmann, who had headed the Department of Tropical Medicine Basic Research at the BNITM since 1998. Bernhard Fleischer was deputy chairman. The third member of the board was Egbert Tannich. In early 2018, Egbert Tannich took up his position as Chairman of the Institute's Board of Directors. In addition to managing director Birgit Müller, Jürgen May and Stephan Günther joined the board. The research groups also underwent restructuring: Egbert Tannich took over the establishment of the "Infection Diagnostics" department. Michael Ramharter was appointed to the W3 professorship "Clinical Tropical Medicine" at the University Hospital Hamburg-Eppendorf and moved to the BNITM with his department "Clinical Research".Today, the research priorities are divided between the Robert Koch Institute (RKI) and the BNITM. While the BNITM is responsible for research abroad, the RKI is responsible for issues on research and hygiene within Germany A branch office of the Institute was located in the hospital of the German mining settlement of Bong Town in the West African state of Liberia , which was closed in the 1990s as a result of the civil war. On 23 February 2015, Health Minister Hermann Gröhe visited the BNITM. As a member of the scientific community Gottfried Wilhelm Leibniz (Wissenschaftsgemeinschaft WGL), the Institute is institutionally funded by the Federal Government and the Federal States as a "research institute of supra-regional importance". Among the population the BNITM is also known as "The Tropical Institute" or is sometimes colloquially referred to as "Tropical Hospital". The German Armed Forces Hospital Hamburg closely cooperates with the BNITM, so that, i.a the Tropical Medicine Department of the German Armed Forces Hospital has been accommodated in the BNITM since 2005. Since 2006 there is no more hospital operation at the BNITM. The Bernhard Nocht Medal for Tropical Medicine is awarded by the Bernhard Nocht Institute and the German Society for Tropical Medicine and Global Health; the winner gives a lecture in Hamburg. Some of the prize winners, such as Walter Kikuth [ de ] and Hans Vogel, also did research at the Bernhard Nocht Institute. At the end of January 2020, Chairman Tannich attracted considerable public attention in Germany when he characterized, on one of the major national TV channels ( ARD ), coronavirus SARS-CoV2 as object of a media hype: "We are surprised at what lengths there is now media coverage, at its intensity, and how much space is assigned to it. We are astonished how often it is repeated again and again." Tannich emphasized "that the danger posed by the virus [SARS-CoV2] is significantly smaller than some thought at the beginning."

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Crimean-Congo haemorrhagic fever

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Reston virus

Reston virus (RESTV) Reston virus (RESTV) is one of six known viruses within the genus Ebolavirus . Reston virus causes Ebola virus disease in non-human primates; unlike the other five ebolaviruses, it is not known to cause disease in humans, but has caused asymptomatic infections. Reston virus was first described in 1990 as a new "strain" of Ebola virus (EBOV). It is the single member of the species Reston ebolavirus , which is included into the genus Ebolavirus , family Filoviridae , order Mononegavirales . Reston virus is named after Reston, Virginia , US, where the virus was first discovered. RESTV was discovered in crab-eating macaques from Hazleton Laboratories (now Labcorp Drug Development) in 1989. This attracted significant media attention due to Reston's location in the Washington metropolitan area and the lethality of a closely related Ebola virus. Despite its status as a level-4 organism, Reston virus is non- pathogenic to humans, though hazardous to monkeys; the perception of its lethality was compounded by the monkey's coinfection with Simian hemorrhagic fever virus (SHFV). Despite ongoing research, the determinants for lack of human pathogenicity are yet to be discovered. Reston virus was first introduced as a new "strain" of Ebola virus in 1990. In 2000, it received the designation Reston Ebola virus and in 2002, the name was changed to Reston ebolavirus. Previous abbreviations for the virus were EBOV-R (for Ebola virus Reston) and most recently REBOV (for Reston Ebola virus or Reston ebolavirus). The virus received its current designation in 2010, when it was renamed Reston virus (RESTV). A virus of the species Reston ebolavirus is a Reston virus (RESTV) if it has the properties of Reston ebolaviruses and if its genome diverges from that of the prototype Reston virus. For example, there exists Reston virus variant Pennsylvania (RESTV/Pen), differing by less than 10% at the nucleotide level. While investigating an outbreak of Simian hemorrhagic fever (SHFV) in November 1989, an electron microscopist from USAMRIID named Thomas W. Geisbert discovered filoviruses similar in appearance to Ebola virus in tissue samples taken from a crab-eating macaque imported from the Philippines to Hazleton Laboratories in Reston, Virginia. The filovirus was further isolated by Dr. Peter Jahrling , and over the period of three months over a third of the monkeys died—at a rate of two or three a day. Blood samples were taken from 178 animal handlers during the incident. Of them, six eventually seroconverted , testing positive using ELISA . They remained, however, asymptomatic. In January 1990, an animal handler at Hazelton cut himself while performing a necropsy on the liver of an infected Cynomolgus . Under the direction of the Centers for Disease Control and Prevention (CDC), the animal handler was placed under surveillance for the duration of the incubation period . When the animal handler failed to become ill, it was concluded that the virus had a low pathogenicity in humans. Following the discovery of a filovirus in crab-eating macaques, an investigation tracing the infection was conducted by the CDC . The monkeys were imported from the Philippines , which had no previous record of SHFV or ebolavirus infections. It was suspected that the monkeys contracted both diseases while in transit aboard KLM Airlines before reaching Reston. Shipments were tracked to New York City , Texas , and Mexico City , none of which produced cases of infection. By January 1990, Hazelton Laboratories recovered from its previous losses and began importing monkeys again from the same establishment in Manila that had provided the original animals. The imported monkeys became infected and were euthanized. In early February the CDC received reports of the disease in Alice, Texas. In March the Division of Quarantine at the CDC secured a temporary ban on the importation of monkeys into the United States from anywhere in the world. Following the announcement of the filovirus disease outbreak in Reston, Virginia, a serosurvey was conducted to assess the prevalence of the infection. Of the several hundred serums received by the CDC, approximately ten percent showed some reaction to ebolavirus antigen—though usually at low levels. Counterintuitively, the majority of the monkeys found positive were from Indonesia . In May 1990, an investigation led by Susan Fisher-Hoch, Steve Ostroff, and Jerry Jennings was sent to Indonesia. During the investigation, it was hypothesized that there could be a cross infection since monkeys suspected of illness were typically placed in gang cages containing up to twenty to thirty other monkeys suspected of illness. Upon arrival they were told that most of the monkeys were imported from the island of Sumatra . The investigation team found no trace of the virus in either case. Following the investigation in Indonesia, an experiment was conducted in the level-4 lab at the CDC campus in DeKalb County , Georgia with thirty-two monkeys: sixteen green monkeys ( Cercopithecus aethiops ) and sixteen crab-eating macaques. Half of the sixteen green monkeys and crab-eating macaques were infected with Reston virus and the other half with Ebola virus. Ebola virus infection was lethal to nearly all monkeys. However, most of the monkeys infected with Reston virus recovered in a month. The surviving monkeys were kept for two years to detect any trace of the virus - none was found. However, the monkeys continued to possess a high level of antibody . Following the test at the CDC campus in DeKalb County, two of the monkeys who had survived Reston virus infection were infected with a very large dose of the Ebola virus in an effort to produce an Ebola vaccine . One of the two monkeys remained resistant; the second died. The physical building in which the outbreak occurred was demolished on 30 May 1995 and a daycare center was constructed in its place. Modern spatial computer simulation indicates that the pathogen could have reached both major airports ( Dulles International Airport and Ronald Reagan Washington National Airport ) in less than 45 minutes assuming direct transmission paths. While investigating an outbreak of Simian hemorrhagic fever (SHFV) in November 1989, an electron microscopist from USAMRIID named Thomas W. Geisbert discovered filoviruses similar in appearance to Ebola virus in tissue samples taken from a crab-eating macaque imported from the Philippines to Hazleton Laboratories in Reston, Virginia. The filovirus was further isolated by Dr. Peter Jahrling , and over the period of three months over a third of the monkeys died—at a rate of two or three a day. Blood samples were taken from 178 animal handlers during the incident. Of them, six eventually seroconverted , testing positive using ELISA . They remained, however, asymptomatic. In January 1990, an animal handler at Hazelton cut himself while performing a necropsy on the liver of an infected Cynomolgus . Under the direction of the Centers for Disease Control and Prevention (CDC), the animal handler was placed under surveillance for the duration of the incubation period . When the animal handler failed to become ill, it was concluded that the virus had a low pathogenicity in humans. Following the discovery of a filovirus in crab-eating macaques, an investigation tracing the infection was conducted by the CDC . The monkeys were imported from the Philippines , which had no previous record of SHFV or ebolavirus infections. It was suspected that the monkeys contracted both diseases while in transit aboard KLM Airlines before reaching Reston. Shipments were tracked to New York City , Texas , and Mexico City , none of which produced cases of infection. By January 1990, Hazelton Laboratories recovered from its previous losses and began importing monkeys again from the same establishment in Manila that had provided the original animals. The imported monkeys became infected and were euthanized. In early February the CDC received reports of the disease in Alice, Texas. In March the Division of Quarantine at the CDC secured a temporary ban on the importation of monkeys into the United States from anywhere in the world. Following the announcement of the filovirus disease outbreak in Reston, Virginia, a serosurvey was conducted to assess the prevalence of the infection. Of the several hundred serums received by the CDC, approximately ten percent showed some reaction to ebolavirus antigen—though usually at low levels. Counterintuitively, the majority of the monkeys found positive were from Indonesia . In May 1990, an investigation led by Susan Fisher-Hoch, Steve Ostroff, and Jerry Jennings was sent to Indonesia. During the investigation, it was hypothesized that there could be a cross infection since monkeys suspected of illness were typically placed in gang cages containing up to twenty to thirty other monkeys suspected of illness. Upon arrival they were told that most of the monkeys were imported from the island of Sumatra . The investigation team found no trace of the virus in either case. Following the investigation in Indonesia, an experiment was conducted in the level-4 lab at the CDC campus in DeKalb County , Georgia with thirty-two monkeys: sixteen green monkeys ( Cercopithecus aethiops ) and sixteen crab-eating macaques. Half of the sixteen green monkeys and crab-eating macaques were infected with Reston virus and the other half with Ebola virus. Ebola virus infection was lethal to nearly all monkeys. However, most of the monkeys infected with Reston virus recovered in a month. The surviving monkeys were kept for two years to detect any trace of the virus - none was found. However, the monkeys continued to possess a high level of antibody . Following the test at the CDC campus in DeKalb County, two of the monkeys who had survived Reston virus infection were infected with a very large dose of the Ebola virus in an effort to produce an Ebola vaccine . One of the two monkeys remained resistant; the second died. The physical building in which the outbreak occurred was demolished on 30 May 1995 and a daycare center was constructed in its place. Modern spatial computer simulation indicates that the pathogen could have reached both major airports ( Dulles International Airport and Ronald Reagan Washington National Airport ) in less than 45 minutes assuming direct transmission paths.

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Crimean-Congo haemorrhagic fever

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Biosafety level

A biosafety level ( BSL ), or pathogen/protection level , is a set of biocontainment precautions required to isolate dangerous biological agents in an enclosed laboratory facility. The levels of containment range from the lowest biosafety level 1 (BSL-1) to the highest at level 4 (BSL-4). In the United States, the Centers for Disease Control and Prevention (CDC) have specified these levels in a publication referred to as BMBL. In the European Union , the same biosafety levels are defined in a directive . In Canada the four levels are known as Containment Levels. Facilities with these designations are also sometimes given as P1 through P4 (for pathogen or protection level), as in the term P3 laboratory . At the lowest level of biosafety, precautions may consist of regular hand-washing and minimal protective equipment. At higher biosafety levels, precautions may include airflow systems, multiple containment rooms, sealed containers, positive pressure personnel suits , established protocols for all procedures, extensive personnel training, and high levels of security to control access to the facility. Health Canada reports that world-wide until 1999 there were recorded over 5,000 cases of accidental laboratory infections and 190 deaths. The first prototype Class III (maximum containment) biosafety cabinet was fashioned in 1943 by Hubert Kaempf Jr., then a U.S. Army soldier, under the direction of Arnold G. Wedum, Director (1944–1969) of Industrial Health and Safety at the United States Army Biological Warfare Laboratories , Camp Detrick , Maryland . Kaempf was tired of his MP duties at Detrick and was able to transfer to the sheet metal department working with the contractor, the H.K. Ferguson Co. On 18 April 1955, fourteen representatives met at Camp Detrick in Frederick, Maryland. The meeting was to share knowledge and experiences regarding biosafety , chemical, radiological, and industrial safety issues that were common to the operations at the three principal biological warfare (BW) laboratories of the U.S. Army. Because of the potential implication of the work conducted at biological warfare laboratories, the conferences were restricted to top level security clearances . Beginning in 1957, these conferences were planned to include non-classified sessions as well as classified sessions to enable broader sharing of biological safety information. It was not until 1964, however, that conferences were held in a government installation not associated with a biological warfare program. Over the next ten years, the biological safety conferences grew to include representatives from all federal agencies that sponsored or conducted research with pathogenic microorganisms. By 1966, it began to include representatives from universities, private laboratories, hospitals, and industrial complexes. Throughout the 1970s, participation in the conferences continued to expand and by 1983 discussions began regarding the creation of a formal organization. The American Biological Safety Association (ABSA) was officially established in 1984 and a constitution and bylaws were drafted the same year. As of 2008, ABSA includes some 1,600 members in its professional association. In 1977, Jim Peacock of the Australian Academy of Science asked Bill Snowdon, then chief of the CSIRO 's Australian Animal Health Laboratory (AAHL) if he could have the newly released United States' National Institutes of Health and the British equivalent requirements for the development of infrastructure for bio-containment reviewed by AAHL personnel with a view to recommending the adoption of one of them by Australian authorities. The review was carried out by CSIRO AAHL Project Manager Bill Curnow and CSIRO Engineer Arthur Jenkins. They drafted outcomes for each of the levels of security. AAHL was notionally classified as "substantially beyond P4". These were adopted by the Australian Academy of Science and became the basis for Australian legislation. It opened in 1985 costing AU$185 million, built on Corio Oval . The Australian Animal Health Laboratory is a Class 4/ P4 Laboratory. In 2003, the Chinese Academy of Sciences approved the construction of mainland China's first BSL-4 laboratory at the Wuhan Institute of Virology (WIV). In 2014, the WIV's National Bio-safety Laboratory was built at a cost of 300 million yuan (US$44 million), in collaboration and with assistance from the French government 's CIRI lab . In 2007 a scientific review paper stated that the Canadian Science Centre for Human and Animal Health , which was designed in the early 1990s, "has become the prototype for modern BSL4 laboratories". Starting with the 2020 COVID-19 pandemic near the facilities of the WIV, work in biocontainment facilities has been politicized, especially in the US Senate for example as the result of Rand Paul 's work. Russia asked questions on 25 October 2022 in the United Nations over the presence in Ukraine of biolabs. In April 2023, Sudan's descent into civil war caused worries at the World Health Organization over its National Public Laboratory as contending factions battled over its area and NPL staff were kicked out in favor of installing a military base at its premises. At the time, the facility contained organisms rated at BSL-2. Biosafety level 1 (BSL-1) is suitable for work with well-characterized agents which do not cause disease in healthy humans. In general, these agents should pose minimal potential hazard to laboratory personnel and the environment. At this level, precautions are limited relative to other levels. Laboratory personnel must wash their hands upon entering and exiting the lab. Research with these agents may be performed on standard open laboratory benches without the use of special containment equipment. However, eating and drinking are generally prohibited in laboratory areas. Potentially infectious material must be decontaminated before disposal, either by adding a chemical such as bleach or isopropanol or by packaging for decontamination elsewhere. Personal protective equipment is only required for circumstances where personnel might be exposed to hazardous material. BSL-1 laboratories must have a door which can be closed to limit access to the lab. However, it is not necessary for BSL-1 labs to be isolated from the general building. This level of biosafety is appropriate for work with several kinds of microorganisms including non-pathogenic strains of Escherichia coli and Staphylococcus , Bacillus subtilis , Saccharomyces cerevisiae and other organisms not suspected to contribute to human disease. Due to the relative ease and safety of maintaining a BSL-1 laboratory, these are the types of laboratories generally used as teaching spaces for high schools and colleges . At this level, all precautions used at Biosafety level 1 are followed, and some additional precautions are taken. BSL-2 differs from BSL-1 in that: Biosafety level 2 is suitable for work involving agents of moderate potential hazard to personnel and the environment. This includes various microbes that cause mild disease to humans, or are difficult to contract via aerosol in a lab setting. Examples of pathogens classified as "Risk Group 2" in the United States include hepatitis A , B , and C viruses, human immunodeficiency virus (HIV), pathogenic strains of Escherichia coli and Staphylococcus , Salmonella , Plasmodium falciparum , and Toxoplasma gondii . Notably, the European Union departs from the United States and classifies HIV and hepatitis B – G as Risk Group 3 agents best handled at BSL-3. Prions , the infectious agents that transmit prion diseases such as vCJD , are typically handled under Biosafety Level 2 or higher. This is due to the lack of any evidence of aerosol transmission and relatively higher infective dose of prion diseases, though some circumstances (such as handling animal-infective prions in a facility which cares for vulnerable animals) would require BSL-3 conditions. Biosafety level 3 is appropriate for work involving microbes which can cause serious and potentially lethal disease via the inhalation route. This type of work can be done in clinical, diagnostic, teaching, research, or production facilities. Here, the precautions undertaken in BSL-1 and BSL-2 labs are followed, as well as additional measures including: In addition, the facility which houses the BSL-3 laboratory must have certain features to ensure appropriate containment. The entrance to the laboratory must be separated from areas of the building with unrestricted traffic flow. Additionally, the laboratory must be behind two sets of self-closing doors (to reduce the risk of aerosols escaping). The construction of the laboratory is such that it can be easily cleaned. Carpets are not permitted, and any seams in the floors, walls, and ceilings are sealed to allow for easy cleaning and decontamination. Additionally, windows must be sealed, and a ventilation system installed which forces air to flow from the "clean" areas of the lab to the areas where infectious agents are handled. Air from the laboratory must be filtered before it can be recirculated. A 2015 study by USA Today journalists identified more than 200 lab sites in the U.S. that were accredited biosafety levels 3 or 4. The Proceedings of a Workshop on "Developing Norms for the Provision of Biological Laboratories in Low-Resource Contexts" provides a list of BSL-3 laboratories in those countries. Biosafety level 3 is commonly used for research and diagnostic work involving various microbes which can be transmitted by aerosols and/or cause severe disease. These include Francisella tularensis , Mycobacterium tuberculosis , Chlamydia psittaci , Venezuelan equine encephalitis virus , Eastern equine encephalitis virus , SARS-CoV-1 , MERS-CoV , Coxiella burnetii , Rift Valley fever virus , Rickettsia rickettsii , several species of Brucella , chikungunya , yellow fever virus , West Nile virus , Yersinia pestis , and SARS-CoV-2 . Biosafety level 4 (BSL-4) is the highest level of biosafety precautions, and is appropriate for work with agents that could easily be aerosol-transmitted within the laboratory and cause severe to fatal disease in humans for which there are no available vaccines or treatments. BSL-4 laboratories are generally set up to be either cabinet laboratories or protective-suit laboratories. In cabinet laboratories, all work must be done within a class III biosafety cabinet . Materials leaving the cabinet must be decontaminated by passing through an autoclave or a tank of disinfectant . The cabinets themselves are required to have seamless edges to allow for easy cleaning. Additionally, the cabinet and all materials within must be free of sharp edges to reduce the risk of damage to the gloves. In a protective-suit laboratory, all work must be done in a class II biosafety cabinet by personnel wearing a positive pressure suit . To exit the BSL-4 laboratory, personnel must pass through a chemical shower for decontamination, then a room for removing the positive-pressure suit, followed by a personal shower. Entry into the BSL-4 laboratory is restricted to trained and authorized individuals, and all persons entering and exiting the laboratory must be recorded. As with BSL-3 laboratories, BSL-4 laboratories must be separated from areas that receive unrestricted traffic. Additionally, airflow is tightly controlled to ensure that air always flows from "clean" areas of the lab to areas where work with infectious agents is being performed. The entrance to the BSL-4 lab must also employ airlocks to minimize the possibility that aerosols from the lab could be removed from the lab. All laboratory waste, including filtered air, water, and trash must also be decontaminated before it can leave the facility. Biosafety level 4 laboratories are used for diagnostic work and research on easily transmitted pathogens which can cause fatal disease. These include a number of viruses known to cause viral hemorrhagic fever such as Marburg virus , Ebola virus , Lassa virus , and Crimean-Congo hemorrhagic fever . Other pathogens handled at BSL-4 include Hendra virus , Nipah virus , and some flaviviruses . Additionally, poorly characterized pathogens which appear closely related to dangerous pathogens are often handled at this level until sufficient data are obtained either to confirm continued work at this level, or to permit working with them at a lower level. This level is also used for work with Variola virus , the causative agent of smallpox , though this work is only performed at the Centers for Disease Control and Prevention in Atlanta, United States, and the State Research Center of Virology and Biotechnology in Koltsovo, Russia. Sample-return missions that bring back to Earth samples obtained from a Category V body must be curated at facilities rated BSL-4. Because the existing BSL-4 facilities in the world do not provide the level of cleanliness necessary to such pristine samples, there is a need to design a facility dedicated to curation of restricted (potentially biohazardous ) extraterrestrial materials . The systems of such facilities must be able to contain unknown biohazards, as the sizes of any putative alien microorganisms are unknown. Ideally, it should filter particles down to 10 nanometers , and release of a particle 50 nanometers or larger is unacceptable under any circumstance. Because NASA and ESA are collaborating on the Mars Sample Return campaign, due to return samples from Mars in the early 2030s, the need for a Sample Receiving Facility (SRF) is becoming more pressing. An SRF is expected to take 7 to 10 years from design to completion, and an additional two years is recommended for the staff to become proficient and accustomed to the facilities. Biosafety level 1 (BSL-1) is suitable for work with well-characterized agents which do not cause disease in healthy humans. In general, these agents should pose minimal potential hazard to laboratory personnel and the environment. At this level, precautions are limited relative to other levels. Laboratory personnel must wash their hands upon entering and exiting the lab. Research with these agents may be performed on standard open laboratory benches without the use of special containment equipment. However, eating and drinking are generally prohibited in laboratory areas. Potentially infectious material must be decontaminated before disposal, either by adding a chemical such as bleach or isopropanol or by packaging for decontamination elsewhere. Personal protective equipment is only required for circumstances where personnel might be exposed to hazardous material. BSL-1 laboratories must have a door which can be closed to limit access to the lab. However, it is not necessary for BSL-1 labs to be isolated from the general building. This level of biosafety is appropriate for work with several kinds of microorganisms including non-pathogenic strains of Escherichia coli and Staphylococcus , Bacillus subtilis , Saccharomyces cerevisiae and other organisms not suspected to contribute to human disease. Due to the relative ease and safety of maintaining a BSL-1 laboratory, these are the types of laboratories generally used as teaching spaces for high schools and colleges . At this level, all precautions used at Biosafety level 1 are followed, and some additional precautions are taken. BSL-2 differs from BSL-1 in that: Biosafety level 2 is suitable for work involving agents of moderate potential hazard to personnel and the environment. This includes various microbes that cause mild disease to humans, or are difficult to contract via aerosol in a lab setting. Examples of pathogens classified as "Risk Group 2" in the United States include hepatitis A , B , and C viruses, human immunodeficiency virus (HIV), pathogenic strains of Escherichia coli and Staphylococcus , Salmonella , Plasmodium falciparum , and Toxoplasma gondii . Notably, the European Union departs from the United States and classifies HIV and hepatitis B – G as Risk Group 3 agents best handled at BSL-3. Prions , the infectious agents that transmit prion diseases such as vCJD , are typically handled under Biosafety Level 2 or higher. This is due to the lack of any evidence of aerosol transmission and relatively higher infective dose of prion diseases, though some circumstances (such as handling animal-infective prions in a facility which cares for vulnerable animals) would require BSL-3 conditions. Biosafety level 3 is appropriate for work involving microbes which can cause serious and potentially lethal disease via the inhalation route. This type of work can be done in clinical, diagnostic, teaching, research, or production facilities. Here, the precautions undertaken in BSL-1 and BSL-2 labs are followed, as well as additional measures including: In addition, the facility which houses the BSL-3 laboratory must have certain features to ensure appropriate containment. The entrance to the laboratory must be separated from areas of the building with unrestricted traffic flow. Additionally, the laboratory must be behind two sets of self-closing doors (to reduce the risk of aerosols escaping). The construction of the laboratory is such that it can be easily cleaned. Carpets are not permitted, and any seams in the floors, walls, and ceilings are sealed to allow for easy cleaning and decontamination. Additionally, windows must be sealed, and a ventilation system installed which forces air to flow from the "clean" areas of the lab to the areas where infectious agents are handled. Air from the laboratory must be filtered before it can be recirculated. A 2015 study by USA Today journalists identified more than 200 lab sites in the U.S. that were accredited biosafety levels 3 or 4. The Proceedings of a Workshop on "Developing Norms for the Provision of Biological Laboratories in Low-Resource Contexts" provides a list of BSL-3 laboratories in those countries. Biosafety level 3 is commonly used for research and diagnostic work involving various microbes which can be transmitted by aerosols and/or cause severe disease. These include Francisella tularensis , Mycobacterium tuberculosis , Chlamydia psittaci , Venezuelan equine encephalitis virus , Eastern equine encephalitis virus , SARS-CoV-1 , MERS-CoV , Coxiella burnetii , Rift Valley fever virus , Rickettsia rickettsii , several species of Brucella , chikungunya , yellow fever virus , West Nile virus , Yersinia pestis , and SARS-CoV-2 . Biosafety level 4 (BSL-4) is the highest level of biosafety precautions, and is appropriate for work with agents that could easily be aerosol-transmitted within the laboratory and cause severe to fatal disease in humans for which there are no available vaccines or treatments. BSL-4 laboratories are generally set up to be either cabinet laboratories or protective-suit laboratories. In cabinet laboratories, all work must be done within a class III biosafety cabinet . Materials leaving the cabinet must be decontaminated by passing through an autoclave or a tank of disinfectant . The cabinets themselves are required to have seamless edges to allow for easy cleaning. Additionally, the cabinet and all materials within must be free of sharp edges to reduce the risk of damage to the gloves. In a protective-suit laboratory, all work must be done in a class II biosafety cabinet by personnel wearing a positive pressure suit . To exit the BSL-4 laboratory, personnel must pass through a chemical shower for decontamination, then a room for removing the positive-pressure suit, followed by a personal shower. Entry into the BSL-4 laboratory is restricted to trained and authorized individuals, and all persons entering and exiting the laboratory must be recorded. As with BSL-3 laboratories, BSL-4 laboratories must be separated from areas that receive unrestricted traffic. Additionally, airflow is tightly controlled to ensure that air always flows from "clean" areas of the lab to areas where work with infectious agents is being performed. The entrance to the BSL-4 lab must also employ airlocks to minimize the possibility that aerosols from the lab could be removed from the lab. All laboratory waste, including filtered air, water, and trash must also be decontaminated before it can leave the facility. Biosafety level 4 laboratories are used for diagnostic work and research on easily transmitted pathogens which can cause fatal disease. These include a number of viruses known to cause viral hemorrhagic fever such as Marburg virus , Ebola virus , Lassa virus , and Crimean-Congo hemorrhagic fever . Other pathogens handled at BSL-4 include Hendra virus , Nipah virus , and some flaviviruses . Additionally, poorly characterized pathogens which appear closely related to dangerous pathogens are often handled at this level until sufficient data are obtained either to confirm continued work at this level, or to permit working with them at a lower level. This level is also used for work with Variola virus , the causative agent of smallpox , though this work is only performed at the Centers for Disease Control and Prevention in Atlanta, United States, and the State Research Center of Virology and Biotechnology in Koltsovo, Russia. Sample-return missions that bring back to Earth samples obtained from a Category V body must be curated at facilities rated BSL-4. Because the existing BSL-4 facilities in the world do not provide the level of cleanliness necessary to such pristine samples, there is a need to design a facility dedicated to curation of restricted (potentially biohazardous ) extraterrestrial materials . The systems of such facilities must be able to contain unknown biohazards, as the sizes of any putative alien microorganisms are unknown. Ideally, it should filter particles down to 10 nanometers , and release of a particle 50 nanometers or larger is unacceptable under any circumstance. Because NASA and ESA are collaborating on the Mars Sample Return campaign, due to return samples from Mars in the early 2030s, the need for a Sample Receiving Facility (SRF) is becoming more pressing. An SRF is expected to take 7 to 10 years from design to completion, and an additional two years is recommended for the staff to become proficient and accustomed to the facilities. Sample-return missions that bring back to Earth samples obtained from a Category V body must be curated at facilities rated BSL-4. Because the existing BSL-4 facilities in the world do not provide the level of cleanliness necessary to such pristine samples, there is a need to design a facility dedicated to curation of restricted (potentially biohazardous ) extraterrestrial materials . The systems of such facilities must be able to contain unknown biohazards, as the sizes of any putative alien microorganisms are unknown. Ideally, it should filter particles down to 10 nanometers , and release of a particle 50 nanometers or larger is unacceptable under any circumstance. Because NASA and ESA are collaborating on the Mars Sample Return campaign, due to return samples from Mars in the early 2030s, the need for a Sample Receiving Facility (SRF) is becoming more pressing. An SRF is expected to take 7 to 10 years from design to completion, and an additional two years is recommended for the staff to become proficient and accustomed to the facilities. According to a U.S. Government Accountability Office (GAO) report published on 4 October 2007, a total of 1,356 CDC/USDA registered BSL-3 facilities were identified throughout the United States. Approximately 36% of these laboratories are located in academia. 15 BSL-4 facilities were identified in the U.S. in 2007, including nine at federal labs. As of May 2021, there are 42 BSL-4 facilities in operation around the world, with a further 17 planned or under construction. The following is a list of existing BSL-4 facilities worldwide.A North Carolina Mosquito & Vector Control Association (NCMVCA) study highlighted safety concerns. In the United States, laboratories can be funded by federal, state, private, non-profit, or academically. The last accounts for 72% of the funding. High-containment labs that are registered with the Centers for Disease Control and Prevention (CDC) and the U.S. Department of Agriculture's (USDA) Select Agent Program must adhere to Department of Defense standards. Since BSL3 and 4 laboratories in the United States are regulated by either the CDC or USDA or another federal agency (depending on the pathogens they handle), no single federal agency is responsible for regulating or tracking the number of these labs. U.S. high-containment laboratories that handle pathogens which are declared as " select agents " must be inspected periodically by the CDC or USDA, adhere to certain standards, and maintain ongoing education on biosecurity and biosafety policies as mandated by law.

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Puumala_orthohantavirus/html

Puumala orthohantavirus

Puumala orthohantavirus ( PUUV ) is a species of Orthohantavirus . Humans infected with the virus may develop a haemorrhagic fever with renal syndrome (HFRS) known as nephropathia epidemica . Puumala orthohantavirus HFRS is lethal in less than 0.5% of the cases. Rarely, PUUV infection can cause Guillain–Barré syndrome . Puumala orthohantavirus was discovered and named in 1980 named after Puumala , a municipality in Finland . The virus is found predominantly in Scandinavia and Finland, although it has also been reported elsewhere in Northern Europe, Poland and Russia . Because the bank vole ( Myodes glareolus ) acts as a reservoir for the virus, nephropathia epidemica cases track with the vole population in a three- to four-year cycle. Humans are infected through inhalation of dust from vole droppings. It has been theorized that Puumala orthohantavirus , unlike other members of the genus Orthohantavirus , may also have lethal effects on its rodent host. In August 2014 an Israeli researcher studying the behavior of the bank vole in Finland died after contracting the Puumala orthohantavirus , which caused a complete breakdown of her immune system.

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Hantaan_orthohantavirus/html

Hantaan orthohantavirus

Hantaan orthohantavirus ( HTNV ) is an enveloped, single-stranded, negative-sense RNA virus species of Old World Orthohantavirus . It is the causative agent of Korean hemorrhagic fever in humans. It is named for the Hantan River in South Korea , and in turn lends the name to its genus Orthohantavirus and family Hantaviridae .Apodemus agrarius , also known as striped field mouse, is the etiological vector of Hantaan orthohantavirus . Transmission is believed to be through inhalation of aerosolized rodent urine and feces. [ citation needed ]In hantavirus induced hemorrhagic fever, incubation time is between two and four weeks in humans before symptoms of infection present. Severity of symptoms depends on the viral load . Like Dobrava-Belgrade virus , Hantaan virus has a mortality rate of 10 to 12%. During the Korean War (1951–1953), more than 3000 American and Korean troops fell ill with kidney failure , bleeding , and shock . The cause remained unknown until 1976 when Karl M. Johnson an American tropical virologist and his colleagues, including Korean virologist, Ho Wang Lee (Lee Ho Wang), isolated Hantaan virus from the lungs of striped field mice.

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Quarantine/html

Quarantine

A quarantine is a restriction on the movement of people , animals and goods which is intended to prevent the spread of disease or pests . It is often used in connection to disease and illness, preventing the movement of those who may have been exposed to a communicable disease , yet do not have a confirmed medical diagnosis . It is distinct from medical isolation , in which those confirmed to be infected with a communicable disease are isolated from the healthy population. Quarantine considerations are often one aspect of border control . [ citation needed ] The concept of quarantine has been known since biblical times, and is known to have been practised through history in various places. Notable quarantines in modern history include the village of Eyam in 1665 during the bubonic plague outbreak in England; East Samoa during the 1918 flu pandemic ; the Diphtheria outbreak during the 1925 serum run to Nome , the 1972 Yugoslav smallpox outbreak , the SARS pandemic, the Ebola pandemic and extensive quarantines applied throughout the world during the COVID-19 pandemic since 2020. Ethical and practical considerations need to be considered when applying quarantine to people. Practice differs from country to country; in some countries, quarantine is just one of many measures governed by legislation relating to the broader concept of biosecurity ; for example, Australian biosecurity is governed by the single overarching Biosecurity Act 2015 .The word quarantine comes from quarantena or quarantaine , meaning "forty days", used in the Venetian language in the 14th and 15th centuries and also in France. The word is designated in the period during which all ships were required to be isolated before passengers and crew could go ashore during the Black Death plague. The quarantena followed the trentino , or "thirty-day isolation" period, first imposed in 1347 in the Republic of Ragusa , Dalmatia (modern Dubrovnik in Croatia). Merriam-Webster gives various meanings to the noun form, including "a period of 40 days", several relating to ships, "a state of enforced isolation", and as "a restriction on the movement of people and goods which is intended to prevent the spread of disease or pests ". The word is also used as a verb. Quarantine is distinct from medical isolation , in which those confirmed to be infected with a communicable disease are isolated from the healthy population. Quarantine may be used interchangeably with cordon sanitaire , and although the terms are related, cordon sanitaire refers to the restriction of movement of people into or out of a defined geographic area, such as a community, in order to prevent an infection from spreading. An early mention of isolation occurs in the Biblical book of Leviticus , written in the 7th century BC or perhaps earlier, which describes the procedure for separating out people infected with the skin disease Tzaraath . The medical nature of this isolation is, however, disputed. As traditional exegesis (dated 700 CE) sees it as a punishment for trespassing one of several negative commandment, most notably Evil Speech . A more recent hypothesis postulates that the infected are required to isolate themselves in order to prevent spread of disease [ citation needed ] (although the Bible does not imply contagiousness of Tzaraath ): Anyone with such a defiling disease must wear torn clothes, let their hair be unkempt, cover the lower part of their face and cry out, "Unclean! Unclean!" As long as they have the disease they remain unclean. They must live alone; they must live outside the camp. [ non-primary source needed ] Moses ordered that dwellings from which infected Jews had gone should be inspected before being occupied again, and that people recovering from contagious disease were not to be allowed to go abroad until examined. [ citation needed ] A hadith attributed to the Islamic prophet Muhammad advised individuals present in a region with a plague outbreak to remain in place, and advised healthy individuals to avoid traveling there. The Persian Muslim polymath Avicenna argued for controlling "the spread of diseases" in his medical encyclopedia The Canon [Al-Qanun] of Medicine, published in 1025. He also recommended quarantine for patients with infectious diseases, especially tuberculosis . Since the sixteenth century, the Ottoman empire has isolated travellers coming from epidemic areas during the Bubonic plague. A quarantine involved isolating healthy travellers for a period of time so that it could be ascertained if they were sick or not. The mandatory quarantine of special groups of patients, including those with leprosy, started early in Islamic history. In the early 8th century the sixth Umayyad caliph Al-Walid I segregated lepers from the general population, with some later sources crediting the caliph with opening a hospital . The separation of lepers from the general population was also practiced in the Moroccan city of Fez, where lepers were relocated to a cave system outside of the city. Dedicated leprosariums were built in the time of the Ottoman sultan Murad II in the 15th century, with some of the facilities operating for centuries. The word "quarantine" originates from quarantena , the Venetian language form, meaning "forty days". This is due to the 40-day isolation of ships and people practised as a measure of disease prevention related to the plague . Between 1348 and 1359, the Black Death wiped out an estimated 30% of Europe's population, and a significant percentage of Asia's population. Such a disaster led governments to establish measures of containment to handle recurrent epidemics. A document from 1377 states that before entering the city-state of Ragusa in Dalmatia (modern Dubrovnik in Croatia), newcomers had to spend 30 days (a trentine ) in a restricted place (originally nearby islands) waiting to see whether the symptoms of Black Death would develop. In 1448 the Venetian Senate prolonged the waiting period to 40 days, thus giving birth to the term "quarantine". The forty-day quarantine proved to be an effective formula for handling outbreaks of the plague. Dubrovnik was the first city in Europe to set up quarantine sites such as the Lazzarettos of Dubrovnik where arriving ship personnel were held for up to 40 days. According to current estimates, the bubonic plague had a 37-day period from infection to death; therefore, the European quarantines would have been highly successful in determining the health of crews from potential trading and supply ships. Other diseases lent themselves to the practice of quarantine before and after the devastation of the plague. Those affected by leprosy were historically isolated long-term from society, and attempts were made to check the spread of syphilis in northern Europe after 1492, the advent of yellow fever in Spain at the beginning of the 19th century, and the arrival of Asiatic cholera in 1831. [ citation needed ] Venice took the lead in measures to check the spread of plague, having appointed three guardians of public health in the first years of the Black Death (1348). The next record of preventive measures comes from Reggio / Modena in 1374. Venice founded the first lazaret (on a small island adjoining the city) in 1403. In 1467 Genoa followed the example of Venice, and in 1476 the old leper hospital of Marseille was converted into a plague hospital. The great lazaret of Marseille, perhaps the most complete of its kind, was founded in 1526 on the island of Pomègues . The practise at all the Mediterranean lazarets did not differ from the English procedure in the Levantine and North African trade. On the arrival of cholera in 1831 some new lazarets were set up at western ports; notably, a very extensive establishment near Bordeaux . Afterwards, they were used for other purposes. [ citation needed ] Epidemics of yellow fever ravaged urban communities in North America throughout the late-eighteenth and early-nineteenth centuries, the best-known examples being the 1793 Philadelphia yellow fever epidemic and outbreaks in Georgia (1856) and Florida (1888). Cholera and smallpox epidemics continued throughout the nineteenth century, and plague epidemics affected Honolulu and San Francisco from 1899 until 1901. State governments generally relied on the cordon sanitaire as a geographic quarantine measure to control the movement of people into and out of affected communities. During the 1918 influenza pandemic, some communities instituted protective sequestration (sometimes referred to as "reverse quarantine") to keep the infected from introducing influenza into healthy populations. Additionally, the nature of the influenza virus that caused the 1918 pandemic gave rise to a public awareness of the dichotomy between "crowd" and "home" diseases. Simply quarantining the sick in isolation was ineffective in halting the spread of the disease, and new quarantine standards that extended regulations to public spaces became increasingly more common. Most Western countries implemented a range of containment strategies, including isolation, surveillance, and the closure of schools, churches, theatres, and public events. People were prevented from entering the Ashanti Empire at border checkpoints if they exhibited symptoms of smallpox. Those who discovered symptoms of the disease after entering Ashanti were quarantined in remote villages. In the 1830s, both the Ottoman Empire and Egypt established new quarantine systems. In 1831, Mehmet Ali of Egypt founded the Quarantine Board in Alexandria. In 1838, the Ottoman government installed the Supreme Council of Health, including the Quarantine Administration, in Istanbul. These two institutions set up permanent quarantines throughout the eastern Mediterranean, based on the western Mediterranean quarantine model. For example, at the port of İzmir , all ships and their cargo would be inspected and those suspected of carrying the plague would be towed to separate docks and their personnel housed in separate buildings for a determined period of time. In Thessaly , along the Greek-Turkish border, all travellers entering and exiting the Ottoman Empire would be quarantined for 9–15 days. Upon appearance of the plague, the quarantine stations would be militarised and the Ottoman army would be involved in border control and disease monitoring . Since 1852, several conferences were held involving European powers, with a view to uniform action in keeping out infection from the East and preventing its spread within Europe. All but that of 1897 were concerned with cholera . No result came of those at Paris (1852), Constantinople (1866), Vienna (1874), and Rome (1885), but each of the subsequent ones doctrine of constructive infection of a ship as coming from a scheduled port, and an approximation to the principles advocated by the United Kingdom for many years. The principal countries which retained the old system at the time were Spain, Portugal, Turkey, Greece, and Russia (the British possessions at the time, Gibraltar, Malta, and Cyprus, being under the same influence). The aim of each international sanitary convention had been to bind the governments to a uniform minimum of preventive action, with further restrictions permissible to individual countries. The minimum specified by international conventions was very nearly the same as the British practice, which had been in turn adapted to continental opinion in the matter of the importation of rags. [ citation needed ] The Venice convention of 30 January 1892 dealt with cholera by the Suez Canal route; that of Dresden of 15 April 1893, with cholera within European countries; that of Paris of 3 April 1894, with cholera by the pilgrim traffic; and that of Venice, on 19 March 1897, was in connection with the outbreak of plague in the East, and the conference met to settle on an international basis the steps to be taken to prevent, if possible, its spread into Europe. An additional convention was signed in Paris on 3 December 1903. A multilateral international sanitary convention was concluded at Paris on 17 January 1912. This convention was most comprehensive and was designated to replace all previous conventions on that matter. It was signed by 40 countries, and consisted of 160 articles. Ratifications by 16 of the signatories were exchanged in Paris on 7 October 1920. Another multilateral convention was signed in Paris on 21 June 1926, to replace that of 1912. It was signed by 58 countries worldwide, and consisted of 172 articles. In Latin America, a series of regional sanitary conventions were concluded. Such a convention was concluded in Rio de Janeiro on 12 June 1904. A sanitary convention between the governments of Argentina, Brazil, Paraguay, and Uruguay was concluded in Montevideo on 21 April 1914. The convention covers cases of Asiatic cholera , oriental plague and yellow fever . It was ratified by the Uruguayan government on 13 October 1914, by the Paraguayan government on 27 September 1917 and by the Brazilian government on 18 January 1921. Sanitary conventions were also concluded between European states. A Soviet-Latvian sanitary convention was signed on 24 June 1922, for which ratifications were exchanged on 18 October 1923. A bilateral sanitary convention was concluded between the governments of Latvia and Poland on 7 July 1922, for which ratifications were exchanged on 7 April 1925. Another was concluded between the governments of Germany and Poland in Dresden on 18 December 1922, and entered into effect on 15 February 1923. Another one was signed between the governments of Poland and Romania on 20 December 1922. Ratifications were exchanged on 11 July 1923. The Polish government also concluded such a convention with the Soviet government on 7 February 1923, for which ratifications were exchanged on 8 January 1924. A sanitary convention was also concluded between the governments of Poland and Czechoslovakia on 5 September 1925, for which ratifications were exchanged on 22 October 1926. A convention was signed between the governments of Germany and Latvia on 9 July 1926, for which ratifications were exchanged on 6 July 1927. In 1897, the incubation period for this disease was determined and this was to be adopted for administrative purposes. The incubation period was comparatively short, some three or four days. After much discussion ten days was accepted by a majority. The principle of disease notification was unanimously adopted. Each government had to notify other governments of the existence of plague within their jurisdictions and state the measures of prevention being carried out to prevent its spread. The area declared infected was limited to the district or village where the disease prevailed, and no locality was deemed to be infected because of the importation into it of a few cases of plague while there has been no spread. It was decided during the prevalence of plague, every country had the right to close its land borders to traffic. At the Red Sea , it was decided after discussion a healthy vessel could pass through the Suez Canal and continue its voyage in the Mediterranean during the incubation period of the disease and that vessels passing through the Canal in quarantine might, subject to the use of the electric light, coal up in quarantine at Port Said by night or by day, and that passengers might embark in quarantine at that port. Infected vessels, if these carry a doctor and a disinfecting stove, have a right to navigate the Canal in quarantine and subject only to the landing of those who have plague. [ citation needed ] In the 20th and 21st centuries, people suspected of carrying infectious diseases have been quarantined, as in the cases of Andrew Speaker (multi-drug-resistant tuberculosis, 2007) and Kaci Hickox (Ebola, 2014). During the 1957–58 influenza pandemic and the 1968 flu pandemic , several countries implemented measures to control spread of the disease. In addition, the World Health Organization applied a global influenza surveillance network. During the 1994 plague in India , many people were quarantined. Vessels and aircraft carrying passengers were fumigated. In the SARS epidemic , thousands of Chinese people were quarantined and checkpoints to take temperatures were set up. Moving infected patients to isolation wards and home-based self-quarantine of people potentially exposed was the main way the Western African Ebola virus epidemic was ended in 2016; members of the 8th WHO Emergency Committee criticised international travel restrictions imposed during the epidemic as ineffective due to difficulty of enforcement, and counterproductive as they slowed down aid efforts. The People's Republic of China has employed mass quarantines – firstly of the city of Wuhan and subsequently of all of the Hubei province (population 55.5 million) – in the coronavirus disease 2019 pandemic . After a few weeks, the Italian government imposed lockdowns for the entire country (more than 60 million people) in an attempt to stop the spread of the disease there . India quarantined itself from the world for a period of one month. Most governments around the world restricted or advised against all non-essential travel to and from countries and areas affected by the outbreak. By late 2020, the virus had already spread within communities in large parts of the world, with many not knowing where or how they were infected. An early mention of isolation occurs in the Biblical book of Leviticus , written in the 7th century BC or perhaps earlier, which describes the procedure for separating out people infected with the skin disease Tzaraath . The medical nature of this isolation is, however, disputed. As traditional exegesis (dated 700 CE) sees it as a punishment for trespassing one of several negative commandment, most notably Evil Speech . A more recent hypothesis postulates that the infected are required to isolate themselves in order to prevent spread of disease [ citation needed ] (although the Bible does not imply contagiousness of Tzaraath ): Anyone with such a defiling disease must wear torn clothes, let their hair be unkempt, cover the lower part of their face and cry out, "Unclean! Unclean!" As long as they have the disease they remain unclean. They must live alone; they must live outside the camp. [ non-primary source needed ] Moses ordered that dwellings from which infected Jews had gone should be inspected before being occupied again, and that people recovering from contagious disease were not to be allowed to go abroad until examined. [ citation needed ] A hadith attributed to the Islamic prophet Muhammad advised individuals present in a region with a plague outbreak to remain in place, and advised healthy individuals to avoid traveling there. The Persian Muslim polymath Avicenna argued for controlling "the spread of diseases" in his medical encyclopedia The Canon [Al-Qanun] of Medicine, published in 1025. He also recommended quarantine for patients with infectious diseases, especially tuberculosis . Since the sixteenth century, the Ottoman empire has isolated travellers coming from epidemic areas during the Bubonic plague. A quarantine involved isolating healthy travellers for a period of time so that it could be ascertained if they were sick or not. The mandatory quarantine of special groups of patients, including those with leprosy, started early in Islamic history. In the early 8th century the sixth Umayyad caliph Al-Walid I segregated lepers from the general population, with some later sources crediting the caliph with opening a hospital . The separation of lepers from the general population was also practiced in the Moroccan city of Fez, where lepers were relocated to a cave system outside of the city. Dedicated leprosariums were built in the time of the Ottoman sultan Murad II in the 15th century, with some of the facilities operating for centuries. The word "quarantine" originates from quarantena , the Venetian language form, meaning "forty days". This is due to the 40-day isolation of ships and people practised as a measure of disease prevention related to the plague . Between 1348 and 1359, the Black Death wiped out an estimated 30% of Europe's population, and a significant percentage of Asia's population. Such a disaster led governments to establish measures of containment to handle recurrent epidemics. A document from 1377 states that before entering the city-state of Ragusa in Dalmatia (modern Dubrovnik in Croatia), newcomers had to spend 30 days (a trentine ) in a restricted place (originally nearby islands) waiting to see whether the symptoms of Black Death would develop. In 1448 the Venetian Senate prolonged the waiting period to 40 days, thus giving birth to the term "quarantine". The forty-day quarantine proved to be an effective formula for handling outbreaks of the plague. Dubrovnik was the first city in Europe to set up quarantine sites such as the Lazzarettos of Dubrovnik where arriving ship personnel were held for up to 40 days. According to current estimates, the bubonic plague had a 37-day period from infection to death; therefore, the European quarantines would have been highly successful in determining the health of crews from potential trading and supply ships. Other diseases lent themselves to the practice of quarantine before and after the devastation of the plague. Those affected by leprosy were historically isolated long-term from society, and attempts were made to check the spread of syphilis in northern Europe after 1492, the advent of yellow fever in Spain at the beginning of the 19th century, and the arrival of Asiatic cholera in 1831. [ citation needed ] Venice took the lead in measures to check the spread of plague, having appointed three guardians of public health in the first years of the Black Death (1348). The next record of preventive measures comes from Reggio / Modena in 1374. Venice founded the first lazaret (on a small island adjoining the city) in 1403. In 1467 Genoa followed the example of Venice, and in 1476 the old leper hospital of Marseille was converted into a plague hospital. The great lazaret of Marseille, perhaps the most complete of its kind, was founded in 1526 on the island of Pomègues . The practise at all the Mediterranean lazarets did not differ from the English procedure in the Levantine and North African trade. On the arrival of cholera in 1831 some new lazarets were set up at western ports; notably, a very extensive establishment near Bordeaux . Afterwards, they were used for other purposes. [ citation needed ]Epidemics of yellow fever ravaged urban communities in North America throughout the late-eighteenth and early-nineteenth centuries, the best-known examples being the 1793 Philadelphia yellow fever epidemic and outbreaks in Georgia (1856) and Florida (1888). Cholera and smallpox epidemics continued throughout the nineteenth century, and plague epidemics affected Honolulu and San Francisco from 1899 until 1901. State governments generally relied on the cordon sanitaire as a geographic quarantine measure to control the movement of people into and out of affected communities. During the 1918 influenza pandemic, some communities instituted protective sequestration (sometimes referred to as "reverse quarantine") to keep the infected from introducing influenza into healthy populations. Additionally, the nature of the influenza virus that caused the 1918 pandemic gave rise to a public awareness of the dichotomy between "crowd" and "home" diseases. Simply quarantining the sick in isolation was ineffective in halting the spread of the disease, and new quarantine standards that extended regulations to public spaces became increasingly more common. Most Western countries implemented a range of containment strategies, including isolation, surveillance, and the closure of schools, churches, theatres, and public events. People were prevented from entering the Ashanti Empire at border checkpoints if they exhibited symptoms of smallpox. Those who discovered symptoms of the disease after entering Ashanti were quarantined in remote villages. In the 1830s, both the Ottoman Empire and Egypt established new quarantine systems. In 1831, Mehmet Ali of Egypt founded the Quarantine Board in Alexandria. In 1838, the Ottoman government installed the Supreme Council of Health, including the Quarantine Administration, in Istanbul. These two institutions set up permanent quarantines throughout the eastern Mediterranean, based on the western Mediterranean quarantine model. For example, at the port of İzmir , all ships and their cargo would be inspected and those suspected of carrying the plague would be towed to separate docks and their personnel housed in separate buildings for a determined period of time. In Thessaly , along the Greek-Turkish border, all travellers entering and exiting the Ottoman Empire would be quarantined for 9–15 days. Upon appearance of the plague, the quarantine stations would be militarised and the Ottoman army would be involved in border control and disease monitoring . Since 1852, several conferences were held involving European powers, with a view to uniform action in keeping out infection from the East and preventing its spread within Europe. All but that of 1897 were concerned with cholera . No result came of those at Paris (1852), Constantinople (1866), Vienna (1874), and Rome (1885), but each of the subsequent ones doctrine of constructive infection of a ship as coming from a scheduled port, and an approximation to the principles advocated by the United Kingdom for many years. The principal countries which retained the old system at the time were Spain, Portugal, Turkey, Greece, and Russia (the British possessions at the time, Gibraltar, Malta, and Cyprus, being under the same influence). The aim of each international sanitary convention had been to bind the governments to a uniform minimum of preventive action, with further restrictions permissible to individual countries. The minimum specified by international conventions was very nearly the same as the British practice, which had been in turn adapted to continental opinion in the matter of the importation of rags. [ citation needed ] The Venice convention of 30 January 1892 dealt with cholera by the Suez Canal route; that of Dresden of 15 April 1893, with cholera within European countries; that of Paris of 3 April 1894, with cholera by the pilgrim traffic; and that of Venice, on 19 March 1897, was in connection with the outbreak of plague in the East, and the conference met to settle on an international basis the steps to be taken to prevent, if possible, its spread into Europe. An additional convention was signed in Paris on 3 December 1903. A multilateral international sanitary convention was concluded at Paris on 17 January 1912. This convention was most comprehensive and was designated to replace all previous conventions on that matter. It was signed by 40 countries, and consisted of 160 articles. Ratifications by 16 of the signatories were exchanged in Paris on 7 October 1920. Another multilateral convention was signed in Paris on 21 June 1926, to replace that of 1912. It was signed by 58 countries worldwide, and consisted of 172 articles. In Latin America, a series of regional sanitary conventions were concluded. Such a convention was concluded in Rio de Janeiro on 12 June 1904. A sanitary convention between the governments of Argentina, Brazil, Paraguay, and Uruguay was concluded in Montevideo on 21 April 1914. The convention covers cases of Asiatic cholera , oriental plague and yellow fever . It was ratified by the Uruguayan government on 13 October 1914, by the Paraguayan government on 27 September 1917 and by the Brazilian government on 18 January 1921. Sanitary conventions were also concluded between European states. A Soviet-Latvian sanitary convention was signed on 24 June 1922, for which ratifications were exchanged on 18 October 1923. A bilateral sanitary convention was concluded between the governments of Latvia and Poland on 7 July 1922, for which ratifications were exchanged on 7 April 1925. Another was concluded between the governments of Germany and Poland in Dresden on 18 December 1922, and entered into effect on 15 February 1923. Another one was signed between the governments of Poland and Romania on 20 December 1922. Ratifications were exchanged on 11 July 1923. The Polish government also concluded such a convention with the Soviet government on 7 February 1923, for which ratifications were exchanged on 8 January 1924. A sanitary convention was also concluded between the governments of Poland and Czechoslovakia on 5 September 1925, for which ratifications were exchanged on 22 October 1926. A convention was signed between the governments of Germany and Latvia on 9 July 1926, for which ratifications were exchanged on 6 July 1927. In 1897, the incubation period for this disease was determined and this was to be adopted for administrative purposes. The incubation period was comparatively short, some three or four days. After much discussion ten days was accepted by a majority. The principle of disease notification was unanimously adopted. Each government had to notify other governments of the existence of plague within their jurisdictions and state the measures of prevention being carried out to prevent its spread. The area declared infected was limited to the district or village where the disease prevailed, and no locality was deemed to be infected because of the importation into it of a few cases of plague while there has been no spread. It was decided during the prevalence of plague, every country had the right to close its land borders to traffic. At the Red Sea , it was decided after discussion a healthy vessel could pass through the Suez Canal and continue its voyage in the Mediterranean during the incubation period of the disease and that vessels passing through the Canal in quarantine might, subject to the use of the electric light, coal up in quarantine at Port Said by night or by day, and that passengers might embark in quarantine at that port. Infected vessels, if these carry a doctor and a disinfecting stove, have a right to navigate the Canal in quarantine and subject only to the landing of those who have plague. [ citation needed ] In the 20th and 21st centuries, people suspected of carrying infectious diseases have been quarantined, as in the cases of Andrew Speaker (multi-drug-resistant tuberculosis, 2007) and Kaci Hickox (Ebola, 2014). During the 1957–58 influenza pandemic and the 1968 flu pandemic , several countries implemented measures to control spread of the disease. In addition, the World Health Organization applied a global influenza surveillance network. During the 1994 plague in India , many people were quarantined. Vessels and aircraft carrying passengers were fumigated. In the SARS epidemic , thousands of Chinese people were quarantined and checkpoints to take temperatures were set up. Moving infected patients to isolation wards and home-based self-quarantine of people potentially exposed was the main way the Western African Ebola virus epidemic was ended in 2016; members of the 8th WHO Emergency Committee criticised international travel restrictions imposed during the epidemic as ineffective due to difficulty of enforcement, and counterproductive as they slowed down aid efforts. The People's Republic of China has employed mass quarantines – firstly of the city of Wuhan and subsequently of all of the Hubei province (population 55.5 million) – in the coronavirus disease 2019 pandemic . After a few weeks, the Italian government imposed lockdowns for the entire country (more than 60 million people) in an attempt to stop the spread of the disease there . India quarantined itself from the world for a period of one month. Most governments around the world restricted or advised against all non-essential travel to and from countries and areas affected by the outbreak. By late 2020, the virus had already spread within communities in large parts of the world, with many not knowing where or how they were infected. Since 1852, several conferences were held involving European powers, with a view to uniform action in keeping out infection from the East and preventing its spread within Europe. All but that of 1897 were concerned with cholera . No result came of those at Paris (1852), Constantinople (1866), Vienna (1874), and Rome (1885), but each of the subsequent ones doctrine of constructive infection of a ship as coming from a scheduled port, and an approximation to the principles advocated by the United Kingdom for many years. The principal countries which retained the old system at the time were Spain, Portugal, Turkey, Greece, and Russia (the British possessions at the time, Gibraltar, Malta, and Cyprus, being under the same influence). The aim of each international sanitary convention had been to bind the governments to a uniform minimum of preventive action, with further restrictions permissible to individual countries. The minimum specified by international conventions was very nearly the same as the British practice, which had been in turn adapted to continental opinion in the matter of the importation of rags. [ citation needed ] The Venice convention of 30 January 1892 dealt with cholera by the Suez Canal route; that of Dresden of 15 April 1893, with cholera within European countries; that of Paris of 3 April 1894, with cholera by the pilgrim traffic; and that of Venice, on 19 March 1897, was in connection with the outbreak of plague in the East, and the conference met to settle on an international basis the steps to be taken to prevent, if possible, its spread into Europe. An additional convention was signed in Paris on 3 December 1903. A multilateral international sanitary convention was concluded at Paris on 17 January 1912. This convention was most comprehensive and was designated to replace all previous conventions on that matter. It was signed by 40 countries, and consisted of 160 articles. Ratifications by 16 of the signatories were exchanged in Paris on 7 October 1920. Another multilateral convention was signed in Paris on 21 June 1926, to replace that of 1912. It was signed by 58 countries worldwide, and consisted of 172 articles. In Latin America, a series of regional sanitary conventions were concluded. Such a convention was concluded in Rio de Janeiro on 12 June 1904. A sanitary convention between the governments of Argentina, Brazil, Paraguay, and Uruguay was concluded in Montevideo on 21 April 1914. The convention covers cases of Asiatic cholera , oriental plague and yellow fever . It was ratified by the Uruguayan government on 13 October 1914, by the Paraguayan government on 27 September 1917 and by the Brazilian government on 18 January 1921. Sanitary conventions were also concluded between European states. A Soviet-Latvian sanitary convention was signed on 24 June 1922, for which ratifications were exchanged on 18 October 1923. A bilateral sanitary convention was concluded between the governments of Latvia and Poland on 7 July 1922, for which ratifications were exchanged on 7 April 1925. Another was concluded between the governments of Germany and Poland in Dresden on 18 December 1922, and entered into effect on 15 February 1923. Another one was signed between the governments of Poland and Romania on 20 December 1922. Ratifications were exchanged on 11 July 1923. The Polish government also concluded such a convention with the Soviet government on 7 February 1923, for which ratifications were exchanged on 8 January 1924. A sanitary convention was also concluded between the governments of Poland and Czechoslovakia on 5 September 1925, for which ratifications were exchanged on 22 October 1926. A convention was signed between the governments of Germany and Latvia on 9 July 1926, for which ratifications were exchanged on 6 July 1927. In 1897, the incubation period for this disease was determined and this was to be adopted for administrative purposes. The incubation period was comparatively short, some three or four days. After much discussion ten days was accepted by a majority. The principle of disease notification was unanimously adopted. Each government had to notify other governments of the existence of plague within their jurisdictions and state the measures of prevention being carried out to prevent its spread. The area declared infected was limited to the district or village where the disease prevailed, and no locality was deemed to be infected because of the importation into it of a few cases of plague while there has been no spread. It was decided during the prevalence of plague, every country had the right to close its land borders to traffic. At the Red Sea , it was decided after discussion a healthy vessel could pass through the Suez Canal and continue its voyage in the Mediterranean during the incubation period of the disease and that vessels passing through the Canal in quarantine might, subject to the use of the electric light, coal up in quarantine at Port Said by night or by day, and that passengers might embark in quarantine at that port. Infected vessels, if these carry a doctor and a disinfecting stove, have a right to navigate the Canal in quarantine and subject only to the landing of those who have plague. [ citation needed ] In the 20th and 21st centuries, people suspected of carrying infectious diseases have been quarantined, as in the cases of Andrew Speaker (multi-drug-resistant tuberculosis, 2007) and Kaci Hickox (Ebola, 2014). During the 1957–58 influenza pandemic and the 1968 flu pandemic , several countries implemented measures to control spread of the disease. In addition, the World Health Organization applied a global influenza surveillance network. During the 1994 plague in India , many people were quarantined. Vessels and aircraft carrying passengers were fumigated. In the SARS epidemic , thousands of Chinese people were quarantined and checkpoints to take temperatures were set up. Moving infected patients to isolation wards and home-based self-quarantine of people potentially exposed was the main way the Western African Ebola virus epidemic was ended in 2016; members of the 8th WHO Emergency Committee criticised international travel restrictions imposed during the epidemic as ineffective due to difficulty of enforcement, and counterproductive as they slowed down aid efforts. The People's Republic of China has employed mass quarantines – firstly of the city of Wuhan and subsequently of all of the Hubei province (population 55.5 million) – in the coronavirus disease 2019 pandemic . After a few weeks, the Italian government imposed lockdowns for the entire country (more than 60 million people) in an attempt to stop the spread of the disease there . India quarantined itself from the world for a period of one month. Most governments around the world restricted or advised against all non-essential travel to and from countries and areas affected by the outbreak. By late 2020, the virus had already spread within communities in large parts of the world, with many not knowing where or how they were infected. Plain yellow, green, and even black flags have been used to symbolise disease in both ships and ports, with the colour yellow having a longer historical precedent, as a colour of marking for houses of infection, previous to its use as a maritime marking colour for disease. The former flag used for the purpose was the "Lima" ( L ) flag, which is a mixture of yellow and black flags previously used. It is sometimes called the "yellow jack" but this was also a name for yellow fever , which probably derives its common name from the flag, not the colour of the victims (cholera ships also used a yellow flag). The plain yellow flag ("Quebec" or Q in international maritime signal flags ) probably derives its letter symbol for its initial use in quarantine , but this flag in modern times indicates the opposite—a ship that 'requests free pratique ', i.e. that declares itself free of quarantinable disease, and requests boarding and routine port inspection. Ships in quarantine today would fly either the Q flag alone, meaning "My vessel is 'healthy' and I request free pratique", or the double Q flag (QQ), meaning "I require health clearance". The quarantining of people often raises questions of civil rights , especially in cases of long confinement or segregation from society, such as that of Mary Mallon (also known as Typhoid Mary), a typhoid fever carrier who was arrested and quarantined in 1907 and later spent the last 23 years and 7 months of her life in medical isolation at Riverside Hospital on North Brother Island . Guidance on when and how human rights can be restricted to prevent the spread of infectious disease is found in the Siracusa Principles , a non-binding document developed by the Siracusa International Institute for Criminal Justice and Human Rights and adopted by the United Nations Economic and Social Council in 1984. The Siracusa Principles state that restrictions on human rights under the International Covenant on Civil and Political Rights must meet standards of legality, evidence-based necessity , proportionality, and gradualism, noting that public health can be used as grounds for limiting certain rights if the state needs to take measures 'aimed at preventing disease or injury or providing care for the sick and injured.' Limitations on rights (such as quarantine) must be 'strictly necessary,' meaning that they must: respond to a pressing public or social need (health) proportionately pursue a legitimate aim (prevent the spread of infectious disease) be the least restrictive means required for achieving the purpose of the limitation be provided for and carried out in accordance with the law be neither arbitrary nor discriminatory only limit rights that are within the jurisdiction of the state seeking to impose the limitation. In addition, when quarantine is imposed, public health ethics specify that: all restrictive actions must be well-supported by data and scientific evidence all information must be made available to the public all actions must be explained clearly to those whose rights are restricted and to the public all actions must be subject to regular review and reconsideration. Finally, the state is ethically obligated to guarantee that: infected people will not be threatened or abused basic needs such as food, water, medical care, and preventive care will be provided communication with loved ones and with caretakers will be permitted constraints on freedom will be applied equally, regardless of social considerations patients will be compensated fairly for economic and material losses, including salary. Quarantine can have adverse psychological effects on the quarantined, including post-traumatic stress , confusion, and anger. According to a "Rapid Review" published in The Lancet in response to the COVID-19 pandemic , "Stressors included longer quarantine duration, infection fears, frustration, boredom, inadequate supplies, inadequate information, financial loss, and stigma. Some researchers have suggested long-lasting effects. In situations where quarantine is deemed necessary, officials should quarantine individuals for no longer than required, provide clear rationale for quarantine and information about protocols, and ensure sufficient supplies are provided. Appeals to altruism by reminding the public about the benefits of quarantine to wider society can be favourable." Although youngsters appear to be less vulnerable to COVID-19 , the side effects of the pandemic can be devastating. Quarantine from the pandemic led to an increase the prevalence of violence in the family, depression, anxiety, and post-traumatic stress disorder. Children and adolescents may be highly exposed to biopsychosocial stressors generated by the pandemic and once population's containment measures to reduce virus spread are required, they could be potentially affected by the disruption in daily life routine as a result of social isolation and their unseasoned ability to conceive and comprehend the short- and long-term consequences of this outbreak. Quarantine periods can be very short, such as in the case of a suspected anthrax attack, in which people are allowed to leave as soon as they shed their potentially contaminated garments and undergo a decontamination shower. For example, an article entitled "Daily News workers quarantined" describes a brief quarantine that lasted until people could be showered in a decontamination tent. The February–March 2003 issue of HazMat Magazine suggests that people be "locked in a room until proper decon could be performed", in the event of "suspect anthrax". [ citation needed ] Standard-Times senior correspondent Steve Urbon (14 February 2003) describes such temporary quarantine powers: Civil rights activists in some cases have objected to people being rounded up, stripped and showered against their will. But Capt. Chmiel said local health authorities have "certain powers to quarantine people". The purpose of such quarantine-for-decontamination is to prevent the spread of contamination and to contain the contamination such that others are not put at risk from a person fleeing a scene where contamination is suspect. It can also be used to limit exposure, as well as eliminate a vector . New developments for quarantine include new concepts in quarantine vehicles such as the ambulance bus , mobile hospitals, and lockdown/invacuation (inverse evacuation) procedures, as well as docking stations for an ambulance bus to dock to a facility under lockdown. Guidance on when and how human rights can be restricted to prevent the spread of infectious disease is found in the Siracusa Principles , a non-binding document developed by the Siracusa International Institute for Criminal Justice and Human Rights and adopted by the United Nations Economic and Social Council in 1984. The Siracusa Principles state that restrictions on human rights under the International Covenant on Civil and Political Rights must meet standards of legality, evidence-based necessity , proportionality, and gradualism, noting that public health can be used as grounds for limiting certain rights if the state needs to take measures 'aimed at preventing disease or injury or providing care for the sick and injured.' Limitations on rights (such as quarantine) must be 'strictly necessary,' meaning that they must: respond to a pressing public or social need (health) proportionately pursue a legitimate aim (prevent the spread of infectious disease) be the least restrictive means required for achieving the purpose of the limitation be provided for and carried out in accordance with the law be neither arbitrary nor discriminatory only limit rights that are within the jurisdiction of the state seeking to impose the limitation. In addition, when quarantine is imposed, public health ethics specify that: all restrictive actions must be well-supported by data and scientific evidence all information must be made available to the public all actions must be explained clearly to those whose rights are restricted and to the public all actions must be subject to regular review and reconsideration. Finally, the state is ethically obligated to guarantee that: infected people will not be threatened or abused basic needs such as food, water, medical care, and preventive care will be provided communication with loved ones and with caretakers will be permitted constraints on freedom will be applied equally, regardless of social considerations patients will be compensated fairly for economic and material losses, including salary. Quarantine can have adverse psychological effects on the quarantined, including post-traumatic stress , confusion, and anger. According to a "Rapid Review" published in The Lancet in response to the COVID-19 pandemic , "Stressors included longer quarantine duration, infection fears, frustration, boredom, inadequate supplies, inadequate information, financial loss, and stigma. Some researchers have suggested long-lasting effects. In situations where quarantine is deemed necessary, officials should quarantine individuals for no longer than required, provide clear rationale for quarantine and information about protocols, and ensure sufficient supplies are provided. Appeals to altruism by reminding the public about the benefits of quarantine to wider society can be favourable." Although youngsters appear to be less vulnerable to COVID-19 , the side effects of the pandemic can be devastating. Quarantine from the pandemic led to an increase the prevalence of violence in the family, depression, anxiety, and post-traumatic stress disorder. Children and adolescents may be highly exposed to biopsychosocial stressors generated by the pandemic and once population's containment measures to reduce virus spread are required, they could be potentially affected by the disruption in daily life routine as a result of social isolation and their unseasoned ability to conceive and comprehend the short- and long-term consequences of this outbreak. Quarantine periods can be very short, such as in the case of a suspected anthrax attack, in which people are allowed to leave as soon as they shed their potentially contaminated garments and undergo a decontamination shower. For example, an article entitled "Daily News workers quarantined" describes a brief quarantine that lasted until people could be showered in a decontamination tent. The February–March 2003 issue of HazMat Magazine suggests that people be "locked in a room until proper decon could be performed", in the event of "suspect anthrax". [ citation needed ] Standard-Times senior correspondent Steve Urbon (14 February 2003) describes such temporary quarantine powers: Civil rights activists in some cases have objected to people being rounded up, stripped and showered against their will. But Capt. Chmiel said local health authorities have "certain powers to quarantine people". The purpose of such quarantine-for-decontamination is to prevent the spread of contamination and to contain the contamination such that others are not put at risk from a person fleeing a scene where contamination is suspect. It can also be used to limit exposure, as well as eliminate a vector . New developments for quarantine include new concepts in quarantine vehicles such as the ambulance bus , mobile hospitals, and lockdown/invacuation (inverse evacuation) procedures, as well as docking stations for an ambulance bus to dock to a facility under lockdown. Biosecurity in Australia is governed by the Biosecurity Act 2015 . The Department of Agriculture, Water and the Environment (DAWE) is responsible for border inspection of products brought into Australia, and assesses the risks the products might harm Australian environment. No person, goods, and vessels are permitted into Australia without clearance from DAFF. Visitors are required to fill in the information card on arriving in Australia. Besides other risk factors, visitors are required to declare what food and products made of wood and other natural materials they have. Visitors who fail to do so may be subject to a fine of A$444, or may face criminal prosecution and be fined up to A$444,000 or imprisonment of up to 10 years. Australia has very strict quarantine standards. Quarantine in northern Australia is especially important because of its proximity to South-East Asia and the Pacific, which have many pests and diseases not present in Australia. For this reason, the region from Cairns to Broome—including the Torres Strait —is the focus for quarantine activities that protect all Australians. As Australia has been geographically isolated from other major continents for millions of years, there is an endemically unique ecosystem free of several severe pests and diseases that are present in many parts of the world. If other products are brought inside along with pests and diseases, it would damage the ecosystem seriously and add millions of costs in the local agricultural businesses. There are three quarantine Acts of Parliament in Canada: Quarantine Act (humans), Health of Animals Act (animals), and Plant Protection Act (vegetations). The first legislation is enforced by the Canada Border Services Agency after a complete rewrite in 2005. The second and third legislations are enforced by the Canadian Food Inspection Agency . If a health emergency exists, the Governor in Council can prohibit importation of anything that it deems necessary under the Quarantine Act . Under the Quarantine Act , all travellers must submit to screening and if they believe they might have come into contact with communicable diseases or vectors , they must disclose their whereabouts to a Border Services Officer . If the officer has reasonable grounds to believe that the traveller is or might have been infected with a communicable disease or refused to provide answers, a quarantine officer (QO) must be called and the person is to be isolated. If a person refuses to be isolated, any peace officer may arrest without warrant. A QO who has reasonable grounds to believe that the traveller has or might have a communicable disease or is infested with vectors, after the medical examination of a traveller, can order him/her into treatment or measures to prevent the person from spreading the disease. QO can detain any traveller who refuses to comply with his/her orders or undergo health assessments as required by law. Under the Health of Animals Act and Plant Protection Act , inspectors can prohibit access to an infected area, dispose or treat any infected or suspected to be infected animals or plants. The Minister can order for compensation to be given if animals/plants were destroyed pursuant to these acts. Each province also enacts its own quarantine/environmental health legislation. Under the Prevention and Control of Disease Ordinance (HK Laws. Chap 599), a health officer may seize articles they believe to be infectious or containing infectious agents. All travellers, if requested, must submit themselves to a health officer. Failure to do so is against the law and is subject to arrest and prosecution. The law allows for health officers who have reasonable grounds to detain, isolate, quarantine anyone or anything believed to be infected, and to restrict any articles from leaving a designated quarantine area. He/she may also order the Civil Aviation Department to prohibit the landing or leaving, embarking or disembarking of an aircraft. This power also extends to land, sea or air crossings. Under the same ordinance, any police officer, health officer, member of the Civil Aid Service , or member of the Auxiliary Medical Service can arrest a person who obstructs or escapes from detention. To reduce the risk of introducing rabies from continental Europe, the United Kingdom used to require that dogs, and most other animals introduced to the country, spend six months in quarantine at an HM Customs and Excise pound; this policy was abolished in 2000 in favour of a scheme generally known as Pet Passports , where animals can avoid quarantine if they have documentation showing they are up to date on their appropriate vaccinations . The plague had disappeared from England for more than thirty years before the practice of quarantine against it was definitely established by the Quarantine Act 1710 ( 9 Ann. ). The first act was called for due to fears that the plague might be imported from Poland and the Baltic region . The second act of 1721 was due to the prevalence of plague at Marseille and other places in Provence, France . It was renewed in 1733 after a new outbreak in continental Europe , and again in 1743, due to an epidemic in Messina . In 1752 a rigorous quarantine clause was introduced into an act regulating trade with the Levant , and various arbitrary orders were issued during the next twenty years to meet the supposed danger of infection from the Baltic region. Although no plague cases ever came to England during that period, the restrictions on traffic became more stringent, and in 1788 a very strict Quarantine Act was passed, with provisions affecting cargoes in particular. The act was revised in 1801 and 1805, and in 1823–24 an elaborate inquiry was followed by an act making quarantine only at discretion of the privy council , which recognised yellow fever or other highly infectious diseases as calling for quarantine, along with plague. The threat of cholera in 1831 was the last occasion in England of the use of quarantine restrictions. Cholera affected every country in Europe, despite all efforts to keep it out. When cholera returned to England in 1849, 1853 and 1865–66, no attempt was made to seal the ports. In 1847 the privy council ordered all arrivals with a clean bill of health from the Black Sea and the Levant to be admitted, provided there had been no case of plague during the voyage, and afterwards the practice of quarantine was discontinued. After the passing of the first Quarantine Act (1710) the protective practices in England were haphazard and arbitrary. In 1721 two vessels carrying cotton goods from Cyprus, then affected by the plague, were ordered to be burned with their cargoes, the owners receiving an indemnity . By the clause in the Levant Trade Act of 1752, ships arriving in the United Kingdom with a "foul bill" (i.e. coming from a country where plague existed) had to return to the lazarets of Malta, Venice, Messina, Livorno, Genoa, or Marseille, to complete a quarantine or to have their cargoes opened and aired. Since 1741 Stangate Creek (on the Medway ) had been the quarantine station but it was available only for vessels with clean bills of health. In 1755 lazarets in the form of floating hulks were established in England for the first time, the cleansing of cargo (particularly by exposure to dews ) having been done previously on the ship's deck. No medical inspections were conducted, but control was the responsibility of the Officers of Royal Customs and quarantine. In 1780, when plague was in Poland, even vessels with grain from the Baltic region had to spend forty days in quarantine, and unpack and air their cargoes, but due to complaints mainly from Edinburgh and Leith , an exception was made for grain after that date. About 1788 an order of the council required every ship liable to quarantine to hoist a yellow flag in the daytime and show a light at the main topmast head at night, in case of meeting any vessel at sea, or upon arriving within four leagues of the coast of Great Britain or Ireland , the Channel Islands , or the Isle of Man . After 1800, ships from plague-affected countries (or with foul bills) were permitted to complete their quarantine in the Medway instead of at a Mediterranean port on the way, and an extensive lazaret was built on Chetney Hill near Chatham (although it was later demolished). The use of floating hulks as lazarets continued as before. In 1800 two ships with hides from Mogador in Morocco were ordered to be sunk with their cargoes at the Nore , the owners receiving an indemnity. Animal hides were suspected of harbouring infections, along with a long list of other items, and these had to be exposed on the ship's deck for twenty-one days or less (six days for each instalment of the cargo), and then transported to the lazaret, where they were opened and aired for another forty days. The whole detention of the vessel was from sixty to sixty-five days, including the time for reshipment of her cargo. Pilots had to pass fifteen days on board a convalescent ship. From 1846 onwards the quarantine establishments in the United Kingdom were gradually reduced, while the last vestige of the British quarantine law was removed by the Public Health Act of 1896, which repealed the Quarantine Act of 1825 (with dependent clauses of other acts), and transferred from the privy council to the Local Government Board the powers to deal with ships arriving infected with yellow fever or plague. The powers to deal with cholera ships had been already transferred by the Public Health Act 1875 . British regulations of 9 November 1896 applied to yellow fever , plague and cholera . Officers of Her Majesty's Customs , as well as of Her Majesty's Coastguard and the Board of Trade (for signalling), were empowered to take the initial steps. They certified in writing the master of a supposedly infected ship, and detained the vessel provisionally for not more than twelve hours, giving notice meanwhile to the port sanitary authority . The medical officer of the port boarded the ship and examined every person in it. Every person found infected was taken to a hospital and quarantined under the orders of the medical officer, and the vessel remained under his orders. Every person suspected could be detained on board for 48 hours or removed to the hospital for a similar period. All others were free to land upon giving the addresses of their destinations to be sent to the respective local authorities, so that the dispersed passengers and crew could be kept individually under observation for a few days. The ship was then disinfected, dead bodies buried at sea, infected clothing, bedding, etc., destroyed or disinfected, and bilge-water and water-ballast pumped out at a suitable distance before the ship entered a dock or basin. Mail was subject to no detention. A stricken ship within 3 miles of the shore had to fly a yellow and black flag at the main mast from sunrise to sunset. In the United States, authority to quarantine people with infectious diseases is split between the state and federal governments. States (and tribal governments recognised by the federal government) have primary authority to quarantine people within their boundaries. Federal jurisdiction only applies to people moving across state or national borders, or people on federal property. Communicable diseases for which apprehension, detention, or conditional release of people are authorised must be specified in Executive Orders of the President. As of 2014, these include Executive Orders 13295 13375, and 13674; the latest executive order specifies the following infectious diseases: cholera , diphtheria , infectious tuberculosis , plague , smallpox , yellow fever , viral haemorrhagic fevers ( Lassa , Marburg , Ebola , Crimean-Congo , South American , and others not yet isolated or named), severe acute respiratory syndromes (SARS), and influenza from a novel or re-emergent source. The Department of Health and Human Services is responsible for quarantine decisions, specifically the Centers for Disease Control and Prevention 's Division of Global Migration and Quarantine . As of 21 March 2017, Centers for Disease Control and Prevention (CDC) regulations specify: All commercial passenger flights must report deaths or illnesses to the CDC. Individuals must apply for a travel permit if they are under a Federal quarantine, isolation, or conditional release order. When an individual who is moving between U.S. states is "reasonably believed to be infected" with a quarantinable communicable disease in a "qualifying stage", the CDC may apprehend or examine that individual for potential infection. This includes new regulatory authority permitting the CDC Director to prohibit the importation of animals or products that pose a threat to public health. The rules: The Division of Global Migration Health (DGMH) of the US Centers for Disease Control (CDC) operates small quarantine facilities at a number of US ports of entry. As of 2014, these included one land crossing (in El Paso, Texas ) and 19 international airports. [note 1] Besides the port of entry where it is located, each station is also responsible for quarantining potentially infected travellers entering through any ports of entry in its assigned region. These facilities are fairly small; each one is operated by a few staff members and capable of accommodating 1–2 travellers for a short observation period. Cost estimates for setting up a temporary larger facility, capable of accommodating 100 to 200 travellers for several weeks, have been published by the Airport Cooperative Research Program (ACRP) in 2008 of the Transportation Research Board . The United States puts immediate quarantines on imported products if a contagious disease is identified and can be traced back to a certain shipment or product. All imports will also be quarantined if the disease appears in other countries. [ citation needed ] According to Title 42 U.S.C. §§264 and 266 Archived 24 September 2015 at the Wayback Machine , these statutes provide the Secretary of Health and Human Services peacetime and wartime authority to control the movement of people into and within the United States to prevent the spread of communicable disease. Quarantine law began in Colonial America in 1663, when in an attempt to curb an outbreak of smallpox , the city of New York established a quarantine. In the 1730s, the city built a quarantine station on the Bedloe's Island . The Philadelphia Lazaretto was the first quarantine hospital in the United States, built in 1799, in Tinicum Township , Delaware County , Pennsylvania. There are similar national landmarks such as the Columbia River Quarantine Station , Swinburne Island and Angel Island . The Pest House in Concord, Massachusetts was used as early as 1752 to quarantine those with cholera, tuberculosis and smallpox. In early June 1832, during the cholera epidemic in New York, Governor Enos Throop called a special session of the Legislature for 21 June, to pass a Public Health Act by both Houses of the State Legislature. It included to a strict quarantine along the Upper and Lower New York-Canadian frontier. In addition, New York City Mayor Walter Browne established a quarantine against all peoples and products of Europe and Asia, which prohibited ships from approaching closer than 300 yards to the city, and all vehicles were ordered to stop 1.5 miles away. The Immigrant Inspection Station on Ellis Island , built in 1892, is often mistakenly assumed to have been a quarantine station, however its marine hospital ( Ellis Island Immigrant Hospital ) only qualified as a contagious disease facility to handle less virulent diseases like measles, trachoma and less advanced stages of tuberculosis and diphtheria; those affected by smallpox, yellow fever, cholera, leprosy or typhoid fever, could neither be received nor treated there. Mary Mallon was quarantined in 1907 under the Greater New York Charter, Sections 1169–1170, which permitted the New York City Board of Health to "remove to a proper place…any person sick with any contagious, pestilential or infectious disease." During the 1918 flu pandemic , people were also quarantined. Most commonly suspect cases of infectious diseases are requested to voluntarily quarantine themselves, and Federal and local quarantine statutes only have been uncommonly invoked since then, including for a suspected smallpox case in 1963. The 1944 Public Health Service Act "to apprehend, detain, and examine certain infected persons who are peculiarly likely to cause the interstate spread of disease" clearly established the federal government 's quarantine authority for the first time. It gave the United States Public Health Service responsibility for preventing the introduction, transmission and spread of communicable diseases from foreign countries into the United States, and expanded quarantine authority to include incoming aircraft. The act states that "...any individual reasonably believed to be infected with a communicable disease in a qualifying stage and...if found to be infected, may be detained for such time and in such manner as may be reasonably necessary." No federal quarantine orders were issued from 1963 until 2020, as American citizens were evacuated from China during the COVID-19 pandemic . Biosecurity in Australia is governed by the Biosecurity Act 2015 . The Department of Agriculture, Water and the Environment (DAWE) is responsible for border inspection of products brought into Australia, and assesses the risks the products might harm Australian environment. No person, goods, and vessels are permitted into Australia without clearance from DAFF. Visitors are required to fill in the information card on arriving in Australia. Besides other risk factors, visitors are required to declare what food and products made of wood and other natural materials they have. Visitors who fail to do so may be subject to a fine of A$444, or may face criminal prosecution and be fined up to A$444,000 or imprisonment of up to 10 years. Australia has very strict quarantine standards. Quarantine in northern Australia is especially important because of its proximity to South-East Asia and the Pacific, which have many pests and diseases not present in Australia. For this reason, the region from Cairns to Broome—including the Torres Strait —is the focus for quarantine activities that protect all Australians. As Australia has been geographically isolated from other major continents for millions of years, there is an endemically unique ecosystem free of several severe pests and diseases that are present in many parts of the world. If other products are brought inside along with pests and diseases, it would damage the ecosystem seriously and add millions of costs in the local agricultural businesses. There are three quarantine Acts of Parliament in Canada: Quarantine Act (humans), Health of Animals Act (animals), and Plant Protection Act (vegetations). The first legislation is enforced by the Canada Border Services Agency after a complete rewrite in 2005. The second and third legislations are enforced by the Canadian Food Inspection Agency . If a health emergency exists, the Governor in Council can prohibit importation of anything that it deems necessary under the Quarantine Act . Under the Quarantine Act , all travellers must submit to screening and if they believe they might have come into contact with communicable diseases or vectors , they must disclose their whereabouts to a Border Services Officer . If the officer has reasonable grounds to believe that the traveller is or might have been infected with a communicable disease or refused to provide answers, a quarantine officer (QO) must be called and the person is to be isolated. If a person refuses to be isolated, any peace officer may arrest without warrant. A QO who has reasonable grounds to believe that the traveller has or might have a communicable disease or is infested with vectors, after the medical examination of a traveller, can order him/her into treatment or measures to prevent the person from spreading the disease. QO can detain any traveller who refuses to comply with his/her orders or undergo health assessments as required by law. Under the Health of Animals Act and Plant Protection Act , inspectors can prohibit access to an infected area, dispose or treat any infected or suspected to be infected animals or plants. The Minister can order for compensation to be given if animals/plants were destroyed pursuant to these acts. Each province also enacts its own quarantine/environmental health legislation.Under the Prevention and Control of Disease Ordinance (HK Laws. Chap 599), a health officer may seize articles they believe to be infectious or containing infectious agents. All travellers, if requested, must submit themselves to a health officer. Failure to do so is against the law and is subject to arrest and prosecution. The law allows for health officers who have reasonable grounds to detain, isolate, quarantine anyone or anything believed to be infected, and to restrict any articles from leaving a designated quarantine area. He/she may also order the Civil Aviation Department to prohibit the landing or leaving, embarking or disembarking of an aircraft. This power also extends to land, sea or air crossings. Under the same ordinance, any police officer, health officer, member of the Civil Aid Service , or member of the Auxiliary Medical Service can arrest a person who obstructs or escapes from detention.To reduce the risk of introducing rabies from continental Europe, the United Kingdom used to require that dogs, and most other animals introduced to the country, spend six months in quarantine at an HM Customs and Excise pound; this policy was abolished in 2000 in favour of a scheme generally known as Pet Passports , where animals can avoid quarantine if they have documentation showing they are up to date on their appropriate vaccinations . The plague had disappeared from England for more than thirty years before the practice of quarantine against it was definitely established by the Quarantine Act 1710 ( 9 Ann. ). The first act was called for due to fears that the plague might be imported from Poland and the Baltic region . The second act of 1721 was due to the prevalence of plague at Marseille and other places in Provence, France . It was renewed in 1733 after a new outbreak in continental Europe , and again in 1743, due to an epidemic in Messina . In 1752 a rigorous quarantine clause was introduced into an act regulating trade with the Levant , and various arbitrary orders were issued during the next twenty years to meet the supposed danger of infection from the Baltic region. Although no plague cases ever came to England during that period, the restrictions on traffic became more stringent, and in 1788 a very strict Quarantine Act was passed, with provisions affecting cargoes in particular. The act was revised in 1801 and 1805, and in 1823–24 an elaborate inquiry was followed by an act making quarantine only at discretion of the privy council , which recognised yellow fever or other highly infectious diseases as calling for quarantine, along with plague. The threat of cholera in 1831 was the last occasion in England of the use of quarantine restrictions. Cholera affected every country in Europe, despite all efforts to keep it out. When cholera returned to England in 1849, 1853 and 1865–66, no attempt was made to seal the ports. In 1847 the privy council ordered all arrivals with a clean bill of health from the Black Sea and the Levant to be admitted, provided there had been no case of plague during the voyage, and afterwards the practice of quarantine was discontinued. After the passing of the first Quarantine Act (1710) the protective practices in England were haphazard and arbitrary. In 1721 two vessels carrying cotton goods from Cyprus, then affected by the plague, were ordered to be burned with their cargoes, the owners receiving an indemnity . By the clause in the Levant Trade Act of 1752, ships arriving in the United Kingdom with a "foul bill" (i.e. coming from a country where plague existed) had to return to the lazarets of Malta, Venice, Messina, Livorno, Genoa, or Marseille, to complete a quarantine or to have their cargoes opened and aired. Since 1741 Stangate Creek (on the Medway ) had been the quarantine station but it was available only for vessels with clean bills of health. In 1755 lazarets in the form of floating hulks were established in England for the first time, the cleansing of cargo (particularly by exposure to dews ) having been done previously on the ship's deck. No medical inspections were conducted, but control was the responsibility of the Officers of Royal Customs and quarantine. In 1780, when plague was in Poland, even vessels with grain from the Baltic region had to spend forty days in quarantine, and unpack and air their cargoes, but due to complaints mainly from Edinburgh and Leith , an exception was made for grain after that date. About 1788 an order of the council required every ship liable to quarantine to hoist a yellow flag in the daytime and show a light at the main topmast head at night, in case of meeting any vessel at sea, or upon arriving within four leagues of the coast of Great Britain or Ireland , the Channel Islands , or the Isle of Man . After 1800, ships from plague-affected countries (or with foul bills) were permitted to complete their quarantine in the Medway instead of at a Mediterranean port on the way, and an extensive lazaret was built on Chetney Hill near Chatham (although it was later demolished). The use of floating hulks as lazarets continued as before. In 1800 two ships with hides from Mogador in Morocco were ordered to be sunk with their cargoes at the Nore , the owners receiving an indemnity. Animal hides were suspected of harbouring infections, along with a long list of other items, and these had to be exposed on the ship's deck for twenty-one days or less (six days for each instalment of the cargo), and then transported to the lazaret, where they were opened and aired for another forty days. The whole detention of the vessel was from sixty to sixty-five days, including the time for reshipment of her cargo. Pilots had to pass fifteen days on board a convalescent ship. From 1846 onwards the quarantine establishments in the United Kingdom were gradually reduced, while the last vestige of the British quarantine law was removed by the Public Health Act of 1896, which repealed the Quarantine Act of 1825 (with dependent clauses of other acts), and transferred from the privy council to the Local Government Board the powers to deal with ships arriving infected with yellow fever or plague. The powers to deal with cholera ships had been already transferred by the Public Health Act 1875 . British regulations of 9 November 1896 applied to yellow fever , plague and cholera . Officers of Her Majesty's Customs , as well as of Her Majesty's Coastguard and the Board of Trade (for signalling), were empowered to take the initial steps. They certified in writing the master of a supposedly infected ship, and detained the vessel provisionally for not more than twelve hours, giving notice meanwhile to the port sanitary authority . The medical officer of the port boarded the ship and examined every person in it. Every person found infected was taken to a hospital and quarantined under the orders of the medical officer, and the vessel remained under his orders. Every person suspected could be detained on board for 48 hours or removed to the hospital for a similar period. All others were free to land upon giving the addresses of their destinations to be sent to the respective local authorities, so that the dispersed passengers and crew could be kept individually under observation for a few days. The ship was then disinfected, dead bodies buried at sea, infected clothing, bedding, etc., destroyed or disinfected, and bilge-water and water-ballast pumped out at a suitable distance before the ship entered a dock or basin. Mail was subject to no detention. A stricken ship within 3 miles of the shore had to fly a yellow and black flag at the main mast from sunrise to sunset. The plague had disappeared from England for more than thirty years before the practice of quarantine against it was definitely established by the Quarantine Act 1710 ( 9 Ann. ). The first act was called for due to fears that the plague might be imported from Poland and the Baltic region . The second act of 1721 was due to the prevalence of plague at Marseille and other places in Provence, France . It was renewed in 1733 after a new outbreak in continental Europe , and again in 1743, due to an epidemic in Messina . In 1752 a rigorous quarantine clause was introduced into an act regulating trade with the Levant , and various arbitrary orders were issued during the next twenty years to meet the supposed danger of infection from the Baltic region. Although no plague cases ever came to England during that period, the restrictions on traffic became more stringent, and in 1788 a very strict Quarantine Act was passed, with provisions affecting cargoes in particular. The act was revised in 1801 and 1805, and in 1823–24 an elaborate inquiry was followed by an act making quarantine only at discretion of the privy council , which recognised yellow fever or other highly infectious diseases as calling for quarantine, along with plague. The threat of cholera in 1831 was the last occasion in England of the use of quarantine restrictions. Cholera affected every country in Europe, despite all efforts to keep it out. When cholera returned to England in 1849, 1853 and 1865–66, no attempt was made to seal the ports. In 1847 the privy council ordered all arrivals with a clean bill of health from the Black Sea and the Levant to be admitted, provided there had been no case of plague during the voyage, and afterwards the practice of quarantine was discontinued. After the passing of the first Quarantine Act (1710) the protective practices in England were haphazard and arbitrary. In 1721 two vessels carrying cotton goods from Cyprus, then affected by the plague, were ordered to be burned with their cargoes, the owners receiving an indemnity . By the clause in the Levant Trade Act of 1752, ships arriving in the United Kingdom with a "foul bill" (i.e. coming from a country where plague existed) had to return to the lazarets of Malta, Venice, Messina, Livorno, Genoa, or Marseille, to complete a quarantine or to have their cargoes opened and aired. Since 1741 Stangate Creek (on the Medway ) had been the quarantine station but it was available only for vessels with clean bills of health. In 1755 lazarets in the form of floating hulks were established in England for the first time, the cleansing of cargo (particularly by exposure to dews ) having been done previously on the ship's deck. No medical inspections were conducted, but control was the responsibility of the Officers of Royal Customs and quarantine. In 1780, when plague was in Poland, even vessels with grain from the Baltic region had to spend forty days in quarantine, and unpack and air their cargoes, but due to complaints mainly from Edinburgh and Leith , an exception was made for grain after that date. About 1788 an order of the council required every ship liable to quarantine to hoist a yellow flag in the daytime and show a light at the main topmast head at night, in case of meeting any vessel at sea, or upon arriving within four leagues of the coast of Great Britain or Ireland , the Channel Islands , or the Isle of Man . After 1800, ships from plague-affected countries (or with foul bills) were permitted to complete their quarantine in the Medway instead of at a Mediterranean port on the way, and an extensive lazaret was built on Chetney Hill near Chatham (although it was later demolished). The use of floating hulks as lazarets continued as before. In 1800 two ships with hides from Mogador in Morocco were ordered to be sunk with their cargoes at the Nore , the owners receiving an indemnity. Animal hides were suspected of harbouring infections, along with a long list of other items, and these had to be exposed on the ship's deck for twenty-one days or less (six days for each instalment of the cargo), and then transported to the lazaret, where they were opened and aired for another forty days. The whole detention of the vessel was from sixty to sixty-five days, including the time for reshipment of her cargo. Pilots had to pass fifteen days on board a convalescent ship. From 1846 onwards the quarantine establishments in the United Kingdom were gradually reduced, while the last vestige of the British quarantine law was removed by the Public Health Act of 1896, which repealed the Quarantine Act of 1825 (with dependent clauses of other acts), and transferred from the privy council to the Local Government Board the powers to deal with ships arriving infected with yellow fever or plague. The powers to deal with cholera ships had been already transferred by the Public Health Act 1875 . British regulations of 9 November 1896 applied to yellow fever , plague and cholera . Officers of Her Majesty's Customs , as well as of Her Majesty's Coastguard and the Board of Trade (for signalling), were empowered to take the initial steps. They certified in writing the master of a supposedly infected ship, and detained the vessel provisionally for not more than twelve hours, giving notice meanwhile to the port sanitary authority . The medical officer of the port boarded the ship and examined every person in it. Every person found infected was taken to a hospital and quarantined under the orders of the medical officer, and the vessel remained under his orders. Every person suspected could be detained on board for 48 hours or removed to the hospital for a similar period. All others were free to land upon giving the addresses of their destinations to be sent to the respective local authorities, so that the dispersed passengers and crew could be kept individually under observation for a few days. The ship was then disinfected, dead bodies buried at sea, infected clothing, bedding, etc., destroyed or disinfected, and bilge-water and water-ballast pumped out at a suitable distance before the ship entered a dock or basin. Mail was subject to no detention. A stricken ship within 3 miles of the shore had to fly a yellow and black flag at the main mast from sunrise to sunset. In the United States, authority to quarantine people with infectious diseases is split between the state and federal governments. States (and tribal governments recognised by the federal government) have primary authority to quarantine people within their boundaries. Federal jurisdiction only applies to people moving across state or national borders, or people on federal property. Communicable diseases for which apprehension, detention, or conditional release of people are authorised must be specified in Executive Orders of the President. As of 2014, these include Executive Orders 13295 13375, and 13674; the latest executive order specifies the following infectious diseases: cholera , diphtheria , infectious tuberculosis , plague , smallpox , yellow fever , viral haemorrhagic fevers ( Lassa , Marburg , Ebola , Crimean-Congo , South American , and others not yet isolated or named), severe acute respiratory syndromes (SARS), and influenza from a novel or re-emergent source. The Department of Health and Human Services is responsible for quarantine decisions, specifically the Centers for Disease Control and Prevention 's Division of Global Migration and Quarantine . As of 21 March 2017, Centers for Disease Control and Prevention (CDC) regulations specify: All commercial passenger flights must report deaths or illnesses to the CDC. Individuals must apply for a travel permit if they are under a Federal quarantine, isolation, or conditional release order. When an individual who is moving between U.S. states is "reasonably believed to be infected" with a quarantinable communicable disease in a "qualifying stage", the CDC may apprehend or examine that individual for potential infection. This includes new regulatory authority permitting the CDC Director to prohibit the importation of animals or products that pose a threat to public health. The rules: The Division of Global Migration Health (DGMH) of the US Centers for Disease Control (CDC) operates small quarantine facilities at a number of US ports of entry. As of 2014, these included one land crossing (in El Paso, Texas ) and 19 international airports. [note 1] Besides the port of entry where it is located, each station is also responsible for quarantining potentially infected travellers entering through any ports of entry in its assigned region. These facilities are fairly small; each one is operated by a few staff members and capable of accommodating 1–2 travellers for a short observation period. Cost estimates for setting up a temporary larger facility, capable of accommodating 100 to 200 travellers for several weeks, have been published by the Airport Cooperative Research Program (ACRP) in 2008 of the Transportation Research Board . The United States puts immediate quarantines on imported products if a contagious disease is identified and can be traced back to a certain shipment or product. All imports will also be quarantined if the disease appears in other countries. [ citation needed ] According to Title 42 U.S.C. §§264 and 266 Archived 24 September 2015 at the Wayback Machine , these statutes provide the Secretary of Health and Human Services peacetime and wartime authority to control the movement of people into and within the United States to prevent the spread of communicable disease. Quarantine law began in Colonial America in 1663, when in an attempt to curb an outbreak of smallpox , the city of New York established a quarantine. In the 1730s, the city built a quarantine station on the Bedloe's Island . The Philadelphia Lazaretto was the first quarantine hospital in the United States, built in 1799, in Tinicum Township , Delaware County , Pennsylvania. There are similar national landmarks such as the Columbia River Quarantine Station , Swinburne Island and Angel Island . The Pest House in Concord, Massachusetts was used as early as 1752 to quarantine those with cholera, tuberculosis and smallpox. In early June 1832, during the cholera epidemic in New York, Governor Enos Throop called a special session of the Legislature for 21 June, to pass a Public Health Act by both Houses of the State Legislature. It included to a strict quarantine along the Upper and Lower New York-Canadian frontier. In addition, New York City Mayor Walter Browne established a quarantine against all peoples and products of Europe and Asia, which prohibited ships from approaching closer than 300 yards to the city, and all vehicles were ordered to stop 1.5 miles away. The Immigrant Inspection Station on Ellis Island , built in 1892, is often mistakenly assumed to have been a quarantine station, however its marine hospital ( Ellis Island Immigrant Hospital ) only qualified as a contagious disease facility to handle less virulent diseases like measles, trachoma and less advanced stages of tuberculosis and diphtheria; those affected by smallpox, yellow fever, cholera, leprosy or typhoid fever, could neither be received nor treated there. Mary Mallon was quarantined in 1907 under the Greater New York Charter, Sections 1169–1170, which permitted the New York City Board of Health to "remove to a proper place…any person sick with any contagious, pestilential or infectious disease." During the 1918 flu pandemic , people were also quarantined. Most commonly suspect cases of infectious diseases are requested to voluntarily quarantine themselves, and Federal and local quarantine statutes only have been uncommonly invoked since then, including for a suspected smallpox case in 1963. The 1944 Public Health Service Act "to apprehend, detain, and examine certain infected persons who are peculiarly likely to cause the interstate spread of disease" clearly established the federal government 's quarantine authority for the first time. It gave the United States Public Health Service responsibility for preventing the introduction, transmission and spread of communicable diseases from foreign countries into the United States, and expanded quarantine authority to include incoming aircraft. The act states that "...any individual reasonably believed to be infected with a communicable disease in a qualifying stage and...if found to be infected, may be detained for such time and in such manner as may be reasonably necessary." No federal quarantine orders were issued from 1963 until 2020, as American citizens were evacuated from China during the COVID-19 pandemic . Communicable diseases for which apprehension, detention, or conditional release of people are authorised must be specified in Executive Orders of the President. As of 2014, these include Executive Orders 13295 13375, and 13674; the latest executive order specifies the following infectious diseases: cholera , diphtheria , infectious tuberculosis , plague , smallpox , yellow fever , viral haemorrhagic fevers ( Lassa , Marburg , Ebola , Crimean-Congo , South American , and others not yet isolated or named), severe acute respiratory syndromes (SARS), and influenza from a novel or re-emergent source. The Department of Health and Human Services is responsible for quarantine decisions, specifically the Centers for Disease Control and Prevention 's Division of Global Migration and Quarantine . As of 21 March 2017, Centers for Disease Control and Prevention (CDC) regulations specify: All commercial passenger flights must report deaths or illnesses to the CDC. Individuals must apply for a travel permit if they are under a Federal quarantine, isolation, or conditional release order. When an individual who is moving between U.S. states is "reasonably believed to be infected" with a quarantinable communicable disease in a "qualifying stage", the CDC may apprehend or examine that individual for potential infection. This includes new regulatory authority permitting the CDC Director to prohibit the importation of animals or products that pose a threat to public health. The rules:The Division of Global Migration Health (DGMH) of the US Centers for Disease Control (CDC) operates small quarantine facilities at a number of US ports of entry. As of 2014, these included one land crossing (in El Paso, Texas ) and 19 international airports. [note 1] Besides the port of entry where it is located, each station is also responsible for quarantining potentially infected travellers entering through any ports of entry in its assigned region. These facilities are fairly small; each one is operated by a few staff members and capable of accommodating 1–2 travellers for a short observation period. Cost estimates for setting up a temporary larger facility, capable of accommodating 100 to 200 travellers for several weeks, have been published by the Airport Cooperative Research Program (ACRP) in 2008 of the Transportation Research Board . The United States puts immediate quarantines on imported products if a contagious disease is identified and can be traced back to a certain shipment or product. All imports will also be quarantined if the disease appears in other countries. [ citation needed ] According to Title 42 U.S.C. §§264 and 266 Archived 24 September 2015 at the Wayback Machine , these statutes provide the Secretary of Health and Human Services peacetime and wartime authority to control the movement of people into and within the United States to prevent the spread of communicable disease.Quarantine law began in Colonial America in 1663, when in an attempt to curb an outbreak of smallpox , the city of New York established a quarantine. In the 1730s, the city built a quarantine station on the Bedloe's Island . The Philadelphia Lazaretto was the first quarantine hospital in the United States, built in 1799, in Tinicum Township , Delaware County , Pennsylvania. There are similar national landmarks such as the Columbia River Quarantine Station , Swinburne Island and Angel Island . The Pest House in Concord, Massachusetts was used as early as 1752 to quarantine those with cholera, tuberculosis and smallpox. In early June 1832, during the cholera epidemic in New York, Governor Enos Throop called a special session of the Legislature for 21 June, to pass a Public Health Act by both Houses of the State Legislature. It included to a strict quarantine along the Upper and Lower New York-Canadian frontier. In addition, New York City Mayor Walter Browne established a quarantine against all peoples and products of Europe and Asia, which prohibited ships from approaching closer than 300 yards to the city, and all vehicles were ordered to stop 1.5 miles away. The Immigrant Inspection Station on Ellis Island , built in 1892, is often mistakenly assumed to have been a quarantine station, however its marine hospital ( Ellis Island Immigrant Hospital ) only qualified as a contagious disease facility to handle less virulent diseases like measles, trachoma and less advanced stages of tuberculosis and diphtheria; those affected by smallpox, yellow fever, cholera, leprosy or typhoid fever, could neither be received nor treated there. Mary Mallon was quarantined in 1907 under the Greater New York Charter, Sections 1169–1170, which permitted the New York City Board of Health to "remove to a proper place…any person sick with any contagious, pestilential or infectious disease." During the 1918 flu pandemic , people were also quarantined. Most commonly suspect cases of infectious diseases are requested to voluntarily quarantine themselves, and Federal and local quarantine statutes only have been uncommonly invoked since then, including for a suspected smallpox case in 1963. The 1944 Public Health Service Act "to apprehend, detain, and examine certain infected persons who are peculiarly likely to cause the interstate spread of disease" clearly established the federal government 's quarantine authority for the first time. It gave the United States Public Health Service responsibility for preventing the introduction, transmission and spread of communicable diseases from foreign countries into the United States, and expanded quarantine authority to include incoming aircraft. The act states that "...any individual reasonably believed to be infected with a communicable disease in a qualifying stage and...if found to be infected, may be detained for such time and in such manner as may be reasonably necessary." No federal quarantine orders were issued from 1963 until 2020, as American citizens were evacuated from China during the COVID-19 pandemic . Eyam was a village in Britain that imposed a cordon sanitaire on itself to stop the spread of the bubonic plague to other communities in 1665. The plague ran its course over 14 months and one account states that it killed at least 260 villagers. The church in Eyam has a record of 273 individuals who were victims of the plague. On 28 July 1814, the convict ship Surry arrived in Sydney Harbour from England. Forty-six people had died of typhoid during the voyage, including 36 convicts, and the ship was placed in quarantine on the North Shore. Convicts were landed, and a camp was established in the immediate vicinity of what is now Jeffrey Street in Kirribilli . This was the first site in Australia to be used for quarantine purposes. Mary Mallon was a cook who was found to be a carrier of Salmonella enterica subsp. enterica , the cause of typhoid fever , and was forcibly isolated from 1907 to 1910. At least 53 cases of the infection were traced to her, and three deaths. Subsequently, she spent a further 23 years in isolation prior to her death in 1938. The presence of the bacteria in her gallbladder was confirmed on autopsy. During the 1918 flu pandemic , the then Governor of American Samoa , John Martin Poyer , imposed a full protective sequestration of the islands from all incoming ships, successfully preventing influenza from infecting the population and thus achieving zero deaths within the territory. In contrast, the neighbouring New Zealand-controlled Western Samoa was among the hardest hit, with a 90% infection rate and over 20% of its adults dying from the disease. This failure by the New Zealand government to prevent and contain the Spanish Flu subsequently rekindled Samoan anti-colonial sentiments that led to its eventual independence. In 1942, during World War II , British forces tested out their biological weapons program on Gruinard Island and infected it with anthrax . Subsequently, a quarantine order was placed on the island. The quarantine was lifted in 1990, when the island was declared safe, and a flock of sheep was released onto the island. Between 24 July 1969 and 9 February 1971, the astronauts of Apollo 11 , Apollo 12 , and Apollo 14 , were quarantined (in each case for a total of 21 days) after returning to Earth, initially where they were recovered, and then were transferred to the Lunar Receiving Laboratory , to prevent possible interplanetary contamination by microorganisms from the Moon . All lunar samples were also held in the biosecure environment of the Lunar Receiving Laboratory for initial assay. The 1972 Yugoslav smallpox outbreak was the final outbreak of smallpox in Europe. The World Health Organization fought the outbreak with extensive quarantine and a cordon sanitaire , and the government instituted martial law . In 2014, Kaci Hickox , a Doctors Without Borders nurse from Maine, legally battled 21-day quarantines imposed by the states of New Jersey and Maine after returning home from treating Ebola patients in Sierra Leone . "Hickox was sequestered in a medical tent for days because New Jersey announced new Ebola regulations the day she arrived. She eventually was allowed to travel to Maine, where the state sought to impose a 'voluntary quarantine' before trying and failing to create a buffer between her and others. A state judge rejected attempts to restrict her movements, saying she posed no threat as long as she wasn't demonstrating any symptoms of Ebola. Hickox said health care professionals like those at the U.S. Centers for Disease Control and Prevention – not politicians like New Jersey Gov. Chris Christie and Maine Gov. Paul LePage – should be in charge of making decisions that are grounded in science, not fear." During the COVID-19 pandemic , multiple governmental actors enacted quarantines in an effort to curb the rapid spread of the virus. Quarantine-like restrictions on movement included curfews and restrictions variously described as stay-at-home orders , shelter-in-place orders, shutdowns or lockdowns . [ citation needed ] On 26 March 2020, 1.7 billion people worldwide were under some form of lockdown , which increased to 2.6 billion people two days later—around a third of the world's population . In Hubei, the origin of the epidemic, a cordon sanitaire was imposed on Wuhan and other major cities in China, affecting around 500 million people, which is unprecedented in scale in human history, to limit the rate of spread of the disease. The 'lockdown' of Wuhan, and subsequently a wider-scale 'lockdown' throughout Hubei province, began on 23 January 2020. At this stage, the spread of the virus in mainland China was running at approximately 50% growth in cases per day. On 8 February, the daily rate of spread fell below 10%. [ citation needed ] As the outbreak spread there, beginning 22 February 2020, a cordon sanitaire was imposed on a group of at least 10 different municipalities in Northern Italy , effectively quarantining more than 50,000 people. This followed a second day when the declared detected cases leapt enormously (the period from 21 to 23 February saw daily increases of 567%, 295% and 90% respectively). A week later the rate of increase of cases in Italy was significantly reduced (the period from 29 February to 4 March saw daily increases of 27%, 50%, 20%, 23%, and 23%). On 8 March 2020, a much wider region of Northern Italy was placed under quarantine restrictions, involving around 16 million people. On the next day, the quarantine was extended to the whole of Italy, effective on 10 March 2020, placing roughly 60 million people under quarantine. A team of Chinese experts, together with some 31 tonnes of supplies, arrived in Rome on 13 March 2020 to help Italy fight the virus. On 22 March 2020, Russia sent nine Ilyushin 76 planes with expert virologists, epidemiologists, medical equipment, and pharmaceuticals in a humanitarian aid operation that Italian media dubbed "From Russia With Love". Eventually the lockdown was extended until 3 May, although starting from 14 April stationery shops, bookshops, and children clothing's shops were allowed to open. On 26 April 2020, the so-called "Phase 2" was announced, to start from 4 May. Movements across regions were still forbidden, while movements between municipalities were allowed only to visit relatives or for work and health reasons. Moreover, closed factories could re-open, but schools, bars, restaurants, and barbers were still closed. As at 4 May 2020, when new cases were running around 0.5%, ( c. 1600 persons) per day and consistently falling, it was expected that museums and retailers might reopen from 18 May, while hairdressers, bars and restaurants were expected to reopen fully on 1 June. Regional lockdowns were subsequently imposed as further waves of the virus spread through the country. As cases of the virus spread to and took hold in more European countries, many followed the earlier examples of China and Italy and began instituting policies of lockdown. Notable among these were Ireland (where schools were closed in mid March for the rest of the month, and limits were set on sizes of meetings), Spain (where a lockdown was announced on 14 March), Czech Republic , Norway , Denmark , Iceland , Poland , Turkey , and France , while the United Kingdom noticeably lagged behind in adopting such measures. As of 18 March 2020, more than 250 million people were in lockdown across Europe. In the immediate context of the start of the pandemic in Wuhan, countries neighbouring or close to China adopted a cautious approach. For example, Sri Lanka, Macau, Hong Kong, Vietnam, Japan, and South Korea had all imposed some degree of lockdown by 19 February. As countries across the world reported escalating case numbers and deaths, more and more countries began to announce travel restrictions and lockdowns. Africa and Latin America were relatively delayed in the spread of the virus, but even on these continents, countries began to impose travel bans and lockdowns. Brazil and Mexico began lockdowns in late February and much of the rest of Latin America followed suit in early March. Much of Africa was on lockdown by the start of April. Kenya, for example, blocked certain international flights and subsequently placed a ban on 'global' meetings. As of 1 April 2020 [ update ] , more than 280 million people, or about 86% of the population, were under some form of lockdown in the United States , 59 million people were in lockdown in South Africa , and 1.3 billion people were in lockdown in India . Eyam was a village in Britain that imposed a cordon sanitaire on itself to stop the spread of the bubonic plague to other communities in 1665. The plague ran its course over 14 months and one account states that it killed at least 260 villagers. The church in Eyam has a record of 273 individuals who were victims of the plague. On 28 July 1814, the convict ship Surry arrived in Sydney Harbour from England. Forty-six people had died of typhoid during the voyage, including 36 convicts, and the ship was placed in quarantine on the North Shore. Convicts were landed, and a camp was established in the immediate vicinity of what is now Jeffrey Street in Kirribilli . This was the first site in Australia to be used for quarantine purposes. Mary Mallon was a cook who was found to be a carrier of Salmonella enterica subsp. enterica , the cause of typhoid fever , and was forcibly isolated from 1907 to 1910. At least 53 cases of the infection were traced to her, and three deaths. Subsequently, she spent a further 23 years in isolation prior to her death in 1938. The presence of the bacteria in her gallbladder was confirmed on autopsy. During the 1918 flu pandemic , the then Governor of American Samoa , John Martin Poyer , imposed a full protective sequestration of the islands from all incoming ships, successfully preventing influenza from infecting the population and thus achieving zero deaths within the territory. In contrast, the neighbouring New Zealand-controlled Western Samoa was among the hardest hit, with a 90% infection rate and over 20% of its adults dying from the disease. This failure by the New Zealand government to prevent and contain the Spanish Flu subsequently rekindled Samoan anti-colonial sentiments that led to its eventual independence. In 1942, during World War II , British forces tested out their biological weapons program on Gruinard Island and infected it with anthrax . Subsequently, a quarantine order was placed on the island. The quarantine was lifted in 1990, when the island was declared safe, and a flock of sheep was released onto the island.Between 24 July 1969 and 9 February 1971, the astronauts of Apollo 11 , Apollo 12 , and Apollo 14 , were quarantined (in each case for a total of 21 days) after returning to Earth, initially where they were recovered, and then were transferred to the Lunar Receiving Laboratory , to prevent possible interplanetary contamination by microorganisms from the Moon . All lunar samples were also held in the biosecure environment of the Lunar Receiving Laboratory for initial assay. The 1972 Yugoslav smallpox outbreak was the final outbreak of smallpox in Europe. The World Health Organization fought the outbreak with extensive quarantine and a cordon sanitaire , and the government instituted martial law .In 2014, Kaci Hickox , a Doctors Without Borders nurse from Maine, legally battled 21-day quarantines imposed by the states of New Jersey and Maine after returning home from treating Ebola patients in Sierra Leone . "Hickox was sequestered in a medical tent for days because New Jersey announced new Ebola regulations the day she arrived. She eventually was allowed to travel to Maine, where the state sought to impose a 'voluntary quarantine' before trying and failing to create a buffer between her and others. A state judge rejected attempts to restrict her movements, saying she posed no threat as long as she wasn't demonstrating any symptoms of Ebola. Hickox said health care professionals like those at the U.S. Centers for Disease Control and Prevention – not politicians like New Jersey Gov. Chris Christie and Maine Gov. Paul LePage – should be in charge of making decisions that are grounded in science, not fear." During the COVID-19 pandemic , multiple governmental actors enacted quarantines in an effort to curb the rapid spread of the virus. Quarantine-like restrictions on movement included curfews and restrictions variously described as stay-at-home orders , shelter-in-place orders, shutdowns or lockdowns . [ citation needed ] On 26 March 2020, 1.7 billion people worldwide were under some form of lockdown , which increased to 2.6 billion people two days later—around a third of the world's population . In Hubei, the origin of the epidemic, a cordon sanitaire was imposed on Wuhan and other major cities in China, affecting around 500 million people, which is unprecedented in scale in human history, to limit the rate of spread of the disease. The 'lockdown' of Wuhan, and subsequently a wider-scale 'lockdown' throughout Hubei province, began on 23 January 2020. At this stage, the spread of the virus in mainland China was running at approximately 50% growth in cases per day. On 8 February, the daily rate of spread fell below 10%. [ citation needed ] As the outbreak spread there, beginning 22 February 2020, a cordon sanitaire was imposed on a group of at least 10 different municipalities in Northern Italy , effectively quarantining more than 50,000 people. This followed a second day when the declared detected cases leapt enormously (the period from 21 to 23 February saw daily increases of 567%, 295% and 90% respectively). A week later the rate of increase of cases in Italy was significantly reduced (the period from 29 February to 4 March saw daily increases of 27%, 50%, 20%, 23%, and 23%). On 8 March 2020, a much wider region of Northern Italy was placed under quarantine restrictions, involving around 16 million people. On the next day, the quarantine was extended to the whole of Italy, effective on 10 March 2020, placing roughly 60 million people under quarantine. A team of Chinese experts, together with some 31 tonnes of supplies, arrived in Rome on 13 March 2020 to help Italy fight the virus. On 22 March 2020, Russia sent nine Ilyushin 76 planes with expert virologists, epidemiologists, medical equipment, and pharmaceuticals in a humanitarian aid operation that Italian media dubbed "From Russia With Love". Eventually the lockdown was extended until 3 May, although starting from 14 April stationery shops, bookshops, and children clothing's shops were allowed to open. On 26 April 2020, the so-called "Phase 2" was announced, to start from 4 May. Movements across regions were still forbidden, while movements between municipalities were allowed only to visit relatives or for work and health reasons. Moreover, closed factories could re-open, but schools, bars, restaurants, and barbers were still closed. As at 4 May 2020, when new cases were running around 0.5%, ( c. 1600 persons) per day and consistently falling, it was expected that museums and retailers might reopen from 18 May, while hairdressers, bars and restaurants were expected to reopen fully on 1 June. Regional lockdowns were subsequently imposed as further waves of the virus spread through the country. As cases of the virus spread to and took hold in more European countries, many followed the earlier examples of China and Italy and began instituting policies of lockdown. Notable among these were Ireland (where schools were closed in mid March for the rest of the month, and limits were set on sizes of meetings), Spain (where a lockdown was announced on 14 March), Czech Republic , Norway , Denmark , Iceland , Poland , Turkey , and France , while the United Kingdom noticeably lagged behind in adopting such measures. As of 18 March 2020, more than 250 million people were in lockdown across Europe. In the immediate context of the start of the pandemic in Wuhan, countries neighbouring or close to China adopted a cautious approach. For example, Sri Lanka, Macau, Hong Kong, Vietnam, Japan, and South Korea had all imposed some degree of lockdown by 19 February. As countries across the world reported escalating case numbers and deaths, more and more countries began to announce travel restrictions and lockdowns. Africa and Latin America were relatively delayed in the spread of the virus, but even on these continents, countries began to impose travel bans and lockdowns. Brazil and Mexico began lockdowns in late February and much of the rest of Latin America followed suit in early March. Much of Africa was on lockdown by the start of April. Kenya, for example, blocked certain international flights and subsequently placed a ban on 'global' meetings. As of 1 April 2020 [ update ] , more than 280 million people, or about 86% of the population, were under some form of lockdown in the United States , 59 million people were in lockdown in South Africa , and 1.3 billion people were in lockdown in India . In Hubei, the origin of the epidemic, a cordon sanitaire was imposed on Wuhan and other major cities in China, affecting around 500 million people, which is unprecedented in scale in human history, to limit the rate of spread of the disease. The 'lockdown' of Wuhan, and subsequently a wider-scale 'lockdown' throughout Hubei province, began on 23 January 2020. At this stage, the spread of the virus in mainland China was running at approximately 50% growth in cases per day. On 8 February, the daily rate of spread fell below 10%. [ citation needed ]As the outbreak spread there, beginning 22 February 2020, a cordon sanitaire was imposed on a group of at least 10 different municipalities in Northern Italy , effectively quarantining more than 50,000 people. This followed a second day when the declared detected cases leapt enormously (the period from 21 to 23 February saw daily increases of 567%, 295% and 90% respectively). A week later the rate of increase of cases in Italy was significantly reduced (the period from 29 February to 4 March saw daily increases of 27%, 50%, 20%, 23%, and 23%). On 8 March 2020, a much wider region of Northern Italy was placed under quarantine restrictions, involving around 16 million people. On the next day, the quarantine was extended to the whole of Italy, effective on 10 March 2020, placing roughly 60 million people under quarantine. A team of Chinese experts, together with some 31 tonnes of supplies, arrived in Rome on 13 March 2020 to help Italy fight the virus. On 22 March 2020, Russia sent nine Ilyushin 76 planes with expert virologists, epidemiologists, medical equipment, and pharmaceuticals in a humanitarian aid operation that Italian media dubbed "From Russia With Love". Eventually the lockdown was extended until 3 May, although starting from 14 April stationery shops, bookshops, and children clothing's shops were allowed to open. On 26 April 2020, the so-called "Phase 2" was announced, to start from 4 May. Movements across regions were still forbidden, while movements between municipalities were allowed only to visit relatives or for work and health reasons. Moreover, closed factories could re-open, but schools, bars, restaurants, and barbers were still closed. As at 4 May 2020, when new cases were running around 0.5%, ( c. 1600 persons) per day and consistently falling, it was expected that museums and retailers might reopen from 18 May, while hairdressers, bars and restaurants were expected to reopen fully on 1 June. Regional lockdowns were subsequently imposed as further waves of the virus spread through the country. As cases of the virus spread to and took hold in more European countries, many followed the earlier examples of China and Italy and began instituting policies of lockdown. Notable among these were Ireland (where schools were closed in mid March for the rest of the month, and limits were set on sizes of meetings), Spain (where a lockdown was announced on 14 March), Czech Republic , Norway , Denmark , Iceland , Poland , Turkey , and France , while the United Kingdom noticeably lagged behind in adopting such measures. As of 18 March 2020, more than 250 million people were in lockdown across Europe. In the immediate context of the start of the pandemic in Wuhan, countries neighbouring or close to China adopted a cautious approach. For example, Sri Lanka, Macau, Hong Kong, Vietnam, Japan, and South Korea had all imposed some degree of lockdown by 19 February. As countries across the world reported escalating case numbers and deaths, more and more countries began to announce travel restrictions and lockdowns. Africa and Latin America were relatively delayed in the spread of the virus, but even on these continents, countries began to impose travel bans and lockdowns. Brazil and Mexico began lockdowns in late February and much of the rest of Latin America followed suit in early March. Much of Africa was on lockdown by the start of April. Kenya, for example, blocked certain international flights and subsequently placed a ban on 'global' meetings. As of 1 April 2020 [ update ] , more than 280 million people, or about 86% of the population, were under some form of lockdown in the United States , 59 million people were in lockdown in South Africa , and 1.3 billion people were in lockdown in India . Self-quarantine (or self-isolation ) is a popular term that emerged during the COVID-19 pandemic , which spread to most countries in 2020. Citizens able to do so were encouraged to stay home to limit the spread of the disease . Health specialists advise that self-quarantine lasts 14 days. Two weeks gives the necessary time for them to determine whether or not they will become ill and become contagious to others. U.S. President John F. Kennedy euphemistically referred to the U.S. Navy's interdiction of shipping en route to Cuba during the Cuban Missile Crisis as a "quarantine" rather than a blockade , because a quarantine is a legal act in peacetime, whereas a blockade is defined as an act of aggression under the U.N. Charter . In computer science, "quarantining" describes putting files infected by computer viruses into a special directory, so as to eliminate the threat they pose, without irreversibly deleting them. The Spanish term for quarantine, (la) cuarentena , refers also to the period of postpartum confinement in which a new mother and her baby are sheltered from the outside world.

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Tanganya_virus/html

Tanganya virus

Tanganya virus (TGNV) is an enveloped , single-stranded, negative-sense RNA virus , possibly of the genus orthohantavirus in the Bunyavirales order. It is the second indigenous Murinae -associated African hantavirus to be discovered. It has a low sequence similarity to other hantaviruses and serologically distinct from other hantaviruses. Its host is Crocidura theresae . The symptoms of the Tanganya virus are high fever, severe headache, and severe malaise. Severe haemorrhagic manifestations may appear between five and seven days from symptom onset. However, not all cases have haemorrhagic signs, and fatal cases usually have some form of bleeding, often from multiple areas.

Wiki

Crimean-Congo haemorrhagic fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/2001/html

2001

2001 ( MMI ) was a common year starting on Monday of the Gregorian calendar , the 2001st year of the Common Era (CE) and Anno Domini (AD) designations, the 1st year of the 3rd millennium and the 21st century , and the 2nd year of the 2000s decade. The year's most prominent event was the September 11 attacks against the United States by Al-Qaeda , which killed 2,977 people and instigated the global war on terror . The United States led a multi-national coalition in an invasion of Afghanistan after the Taliban government was unable to extradite Al-Qaeda leader Osama bin Laden within 24 hours. Other international conflicts in 2001 were the standoff between India and Pakistan as well as the Second Intifada between Israel and Palestine. Internal conflicts began in Macedonia , in the Central African Republic , and in Guinea . Political challenges or violent conflicts caused changes in leadership in Argentina, the Democratic Republic of the Congo, Indonesia, Nepal, and the Philippines. 2001 was the second hottest year on record at the time, which was amplified by the end of a years-long La Niña . The Atlantic and Pacific tropical storm seasons were both more active than usual. The deadly Bhuj Earthquake took place in Gujarat on January 26, while the strongest earthquake in 36 years took place in Peru on June 23. A potential health crisis occurred when a major outbreak of foot-and-mouth disease spread among British livestock, bringing about the deaths of millions of animals. Four hominid species were described or proposed, and several major archaeological finds took place, including a set of terracotta citizens near the Terracotta Army . The pygmy three-toed sloth was also first described in 2001. The year had the fewest successful orbital spaceflights since 1963, with eight crewed missions. Successes in space exploration included the landing of NEAR Shoemaker on an asteroid and the arrival of 2001 Mars Odyssey on Mars. Politics and religion in the final months of 2001 focused intently on the Muslim world and Islamic terrorism after the September 11 attacks. The Catholic Church was active in 2001, as Pope John Paul II went on several goodwill trips to meet with non-Catholic religious groups and investigations of sexual abuse cases among the church's priests began. Former Serbian president Slobodan Milošević was arrested and became the first head of state to be charged with crimes against humanity by an international body. The 27th G8 summit took place in Genoa and was met by 200,000 protestors, where one was killed . 2001 took place during a minor recession among developed and developing nations, with only middle income nations avoiding an economic downturn. The recession saw economic crises take place in Argentina and in Turkey . American energy company Enron and the European airlines Sabena and Swissair all ended operations in 2001. Popular culture in 2001 saw the beginnings of the Harry Potter and The Lord of the Rings film franchises, the development of the iPod and iTunes for music, and the release of three major video game systems. The year also saw the release of Mac OS X and Windows XP .The world population on January 1, 2001, was estimated to be 6.190 billion people and increased to 6.272 billion people by January 1, 2002. An estimated 133.9 million births and 52.1 million deaths took place in 2001. The average global life expectancy was 66.8 years, an increase of 0.3 years from 2000. The rate of child mortality was 7.32%, a decrease of 0.26 pp from 2000. 28.25% of people were living in extreme poverty , a decrease of 0.88pp from 2000. There were approximately 12 million global refugees in 2001. 500,000 were settled over the course of the year, but about the same number of people were displaced in other locations, causing the number of refugees to remain largely unchanged. The largest sources of refugees were from Afghanistan and Macedonia. The number of internally displaced persons decreased from 21.8 million to 19.8 million in 2001, with the most affected areas being Afghanistan, Colombia, and Liberia. There were 34 active armed conflicts in 28 countries in 2001, the total numbers remaining unchanged from 2000. The majority of these conflicts took place in Africa and Asia: 14 occurred in Africa and 13 occurred in Asia. 15 were classified as "major armed conflicts" [lower-alpha 1] by the Stockholm International Peace Research Institute . : 21 Four new armed conflicts emerged in 2001: the insurgency in Macedonia , the attempted coup in the Central African Republic , the United States invasion of Afghanistan , and the entry of Sierra Leone's Revolutionary United Front into the RFDG Insurgency in Guinea. The Sierra Leone Civil War was the only conflict that ended in 2001. : 21 The Second Congo War continued with the assassination of President Laurent-Désiré Kabila on January 16. : 29 The 1999 ceasefire was mostly respected by the government and the various rebel groups, and United Nations ceasefire monitors established a presence throughout the year. : 30 The Algerian Civil War , the Angolan Civil War , and the Burundian Civil War all saw continued fighting between governments and rebels in Africa. : 24–29 The latter began the peace process through a provisional government on November 1. : 27 The Second Sudanese Civil War between the ruling National Islamic Front and various other groups escalated in 2001. : 37 This included a sub-conflict, the War of the Peters , which continued into 2001 until a ceasefire was negotiated in August. Two failed coup attempts took place in 2001: a group of junior officers sought to overthrow President Pierre Buyoya in Burundi while he was out of the country on April 18, : 218 and André Kolingba , a former president of the Central African Republic, led a military coup against his successor Ange-Félix Patassé on May 28, causing several days of violence. : 249 Several conflicts continued in Indonesia, though the insurgency in Aceh between the Indonesian government and the Free Aceh Movement was the only one to see widespread violence in 2001, as the war significantly escalated after the end of a ceasefire and breakdown of peace talks. : 46–47 The New People's Army rebellion saw two ceasefires between the Philippine government and the New People's Army , separated by a brief surge of heavy fighting after the assassination of a member of parliament. A ceasefire was also established with the nation's other insurgent group, the Moro Islamic Liberation Front . : 49 In Myanmar, the Karen conflict continued, and the insurgency of the Shan State resumed hostilities after a temporary peace in 1999. The Tamil Tigers declared a ceasefire and requested peace talks during the Eelam War III in Sri Lanka, : 50 but hostilities resumed on April 25, and the Tamil Tigers launched several suicide attacks in July, including the Bandaranaike Airport attack . : 51 The Nepalese Civil War also saw increased hostilities in 2001. The only major conflict in Europe was the Second Chechen War between the Russian government and the separatist Chechen Republic of Ichkeria . Russian forces controlled the republic's population centers, but Chechen forces continued to use guerrilla warfare . : 53 Macedonia saw a smaller scale conflict between the Macedonian government and the National Liberation Army (NLA), which sought reform for the status of Albanian people in Macedonia. The deployment of NATO peacekeeping forces to Macedonia was authorized on August 21. Yugoslavia similarly saw an insurgency by Albanian rebels, but the conflict did not escalate. : 53 The only major conflict in South America was the Colombian conflict between the Colombian government and various far-left and far-right groups. : 58 The United Self-Defense Forces of Colombia expanded into Ecuador in 2001 and carried out attacks on Ecuadorian citizens. : 60 The 2001–2002 India–Pakistan standoff was the only conflict between two national governments in 2001. The territorial dispute over the region of Kashmir consisted primarily of small scale attacks by militant groups until two attacks on Indian legislature buildings: one in October and one in December . The latter provoked a major escalation of troop deployments with preparations for a major war. : 46 The Second Intifada continued from the previous year between Israel and Palestine. : 55 The conflict escalated into an undeclared war in which Palestinian militants targeted Israeli civilians with weapons and suicide bombers with the Israeli military responding with fighter jets and missile strikes against Palestinians. : 279 Every ceasefire ended within a day of its establishment. : 56 The September 11 attacks were carried out by Al-Qaeda when 19 terrorists hijacked four commercial airplanes and crashed two of them into the World Trade Center , one into the Pentagon , and one near Stonycreek Township, Pennsylvania . 2,977 people were killed; the attacks and the subsequent global war on terror are widely recognized as events that defined 2001. : 1 : 8 This was internationally recognized as an armed attack against the United States under the UN charter , and NATO invoked Article 5 of the North Atlantic Treaty for the first time in its history. : 491 The Afghan Civil War between the de jure Northern Alliance government and the de facto Taliban government continued from previous years. : 39 When the Taliban refused to extradite Al-Qaeda leader Osama bin Laden , the United States led a multi-national coalition in an invasion of Afghanistan on 7 October. : 41 The American-led coalition and the Northern Alliance captured Afghan cities until the Taliban surrendered to the Northern Alliance in Kandahar on December 6. : 42 The American-led coalition attacked the Al-Qaeda headquarters in Tora Bora in December, but Al-Qaeda's leadership had gone into hiding. An interim government of Afghanistan led by Hamid Karzai was formed on December 22. : 42–43The Second Congo War continued with the assassination of President Laurent-Désiré Kabila on January 16. : 29 The 1999 ceasefire was mostly respected by the government and the various rebel groups, and United Nations ceasefire monitors established a presence throughout the year. : 30 The Algerian Civil War , the Angolan Civil War , and the Burundian Civil War all saw continued fighting between governments and rebels in Africa. : 24–29 The latter began the peace process through a provisional government on November 1. : 27 The Second Sudanese Civil War between the ruling National Islamic Front and various other groups escalated in 2001. : 37 This included a sub-conflict, the War of the Peters , which continued into 2001 until a ceasefire was negotiated in August. Two failed coup attempts took place in 2001: a group of junior officers sought to overthrow President Pierre Buyoya in Burundi while he was out of the country on April 18, : 218 and André Kolingba , a former president of the Central African Republic, led a military coup against his successor Ange-Félix Patassé on May 28, causing several days of violence. : 249 Several conflicts continued in Indonesia, though the insurgency in Aceh between the Indonesian government and the Free Aceh Movement was the only one to see widespread violence in 2001, as the war significantly escalated after the end of a ceasefire and breakdown of peace talks. : 46–47 The New People's Army rebellion saw two ceasefires between the Philippine government and the New People's Army , separated by a brief surge of heavy fighting after the assassination of a member of parliament. A ceasefire was also established with the nation's other insurgent group, the Moro Islamic Liberation Front . : 49 In Myanmar, the Karen conflict continued, and the insurgency of the Shan State resumed hostilities after a temporary peace in 1999. The Tamil Tigers declared a ceasefire and requested peace talks during the Eelam War III in Sri Lanka, : 50 but hostilities resumed on April 25, and the Tamil Tigers launched several suicide attacks in July, including the Bandaranaike Airport attack . : 51 The Nepalese Civil War also saw increased hostilities in 2001. The only major conflict in Europe was the Second Chechen War between the Russian government and the separatist Chechen Republic of Ichkeria . Russian forces controlled the republic's population centers, but Chechen forces continued to use guerrilla warfare . : 53 Macedonia saw a smaller scale conflict between the Macedonian government and the National Liberation Army (NLA), which sought reform for the status of Albanian people in Macedonia. The deployment of NATO peacekeeping forces to Macedonia was authorized on August 21. Yugoslavia similarly saw an insurgency by Albanian rebels, but the conflict did not escalate. : 53 The only major conflict in South America was the Colombian conflict between the Colombian government and various far-left and far-right groups. : 58 The United Self-Defense Forces of Colombia expanded into Ecuador in 2001 and carried out attacks on Ecuadorian citizens. : 60The 2001–2002 India–Pakistan standoff was the only conflict between two national governments in 2001. The territorial dispute over the region of Kashmir consisted primarily of small scale attacks by militant groups until two attacks on Indian legislature buildings: one in October and one in December . The latter provoked a major escalation of troop deployments with preparations for a major war. : 46 The Second Intifada continued from the previous year between Israel and Palestine. : 55 The conflict escalated into an undeclared war in which Palestinian militants targeted Israeli civilians with weapons and suicide bombers with the Israeli military responding with fighter jets and missile strikes against Palestinians. : 279 Every ceasefire ended within a day of its establishment. : 56 The September 11 attacks were carried out by Al-Qaeda when 19 terrorists hijacked four commercial airplanes and crashed two of them into the World Trade Center , one into the Pentagon , and one near Stonycreek Township, Pennsylvania . 2,977 people were killed; the attacks and the subsequent global war on terror are widely recognized as events that defined 2001. : 1 : 8 This was internationally recognized as an armed attack against the United States under the UN charter , and NATO invoked Article 5 of the North Atlantic Treaty for the first time in its history. : 491 The Afghan Civil War between the de jure Northern Alliance government and the de facto Taliban government continued from previous years. : 39 When the Taliban refused to extradite Al-Qaeda leader Osama bin Laden , the United States led a multi-national coalition in an invasion of Afghanistan on 7 October. : 41 The American-led coalition and the Northern Alliance captured Afghan cities until the Taliban surrendered to the Northern Alliance in Kandahar on December 6. : 42 The American-led coalition attacked the Al-Qaeda headquarters in Tora Bora in December, but Al-Qaeda's leadership had gone into hiding. An interim government of Afghanistan led by Hamid Karzai was formed on December 22. : 42–43The September 11 attacks were carried out by Al-Qaeda when 19 terrorists hijacked four commercial airplanes and crashed two of them into the World Trade Center , one into the Pentagon , and one near Stonycreek Township, Pennsylvania . 2,977 people were killed; the attacks and the subsequent global war on terror are widely recognized as events that defined 2001. : 1 : 8 This was internationally recognized as an armed attack against the United States under the UN charter , and NATO invoked Article 5 of the North Atlantic Treaty for the first time in its history. : 491 The Afghan Civil War between the de jure Northern Alliance government and the de facto Taliban government continued from previous years. : 39 When the Taliban refused to extradite Al-Qaeda leader Osama bin Laden , the United States led a multi-national coalition in an invasion of Afghanistan on 7 October. : 41 The American-led coalition and the Northern Alliance captured Afghan cities until the Taliban surrendered to the Northern Alliance in Kandahar on December 6. : 42 The American-led coalition attacked the Al-Qaeda headquarters in Tora Bora in December, but Al-Qaeda's leadership had gone into hiding. An interim government of Afghanistan led by Hamid Karzai was formed on December 22. : 42–43New buildings constructed or opened in 2001 include the Bibliotheca Alexandrina in Alexandria , : 163 the Sendai Mediatheque in Sendai , the DG Bank building in Berlin , the SEG Apartment Tower [ de ] in Vienna , and Aurora Place in Sydney . : 164 Museums that opened in 2001 include the Jewish Museum Berlin designed by Daniel Libeskind , the National Museum of Australia designed by Howard Raggatt in Canberra , the Changi Chapel and Museum in Singapore, the Neue Galerie New York , and the Apartheid Museum in Johannesburg . : 233 Prominent renovations made in 2001 include the Queen Elizabeth II Great Court in the British Museum : 163 and the entrance wing of the Milwaukee Art Museum . : 164 Preservation efforts were also completed on the Leaning Tower of Pisa , and it reopened to the public on December 15 after 12 years of reconstruction. Damaged and destroyed buildings included the World Trade Center buildings which were destroyed in the September 11 attacks, : 527 and the Biblioteca Gallardo in El Salvador, which was destroyed in an earthquake. : 232 The 49th Venice Biennale shifted from traditional paintings and sculptures in 2001, giving an increased focus to film and architectural sculpture. : 525 : 167 Among art sales, Avant-garde works sold well, with the highest earning being Gerhard Richter 's painting of candles, which sold for US$5.4 million. : 525 The fashion industry saw a decline that was exacerbated by the September 11 attacks. After the attacks and the subsequent war in Afghanistan, styles with military or otherwise violent iconography were phased out. : 219–220 Improvements in inkjet printing made high resolution photography more practical. Japanese photographer Hiroshi Sugimoto exhibited his photographs of wax statues of historical figures to provoke questions about the nature of artistic depiction. : 171 Several iconic works of photojournalism were produced during the September 11 attacks, including The Falling Man and Raising the Flag at Ground Zero . The Sphere was the only artwork to be recovered from the site, and the sculpture continued to be displayed in its damaged form as a memorial. The most popular exhibition in 2001 was artwork depicting Jacqueline Kennedy 's time as first lady of the United States , followed closely by an exhibition for Johannes Vermeer and the Delft School , both at the Metropolitan Museum of Art . Each saw over 500,000 visitors. : 525 Other exhibitions in 2001 were held in honor of visual artists such as Jacob Lawrence , Clyfford Still , Thomas Eakins , Dan Graham , Henri Rousseau , Paul Signac , Gustav Klimt , Marc Chagall , Raymond Hains , Johannes Vermeer , William Blake ; architects such as Ludwig Mies van der Rohe , Rudolph Schindler , and Frank Gehry ; and photographers such as Walker Evans and August Sander . : 168–170 2001 was the first year in which architecture exhibitions saw major success in the art world. : 525 The highest-grossing films in 2001 were Harry Potter and the Philosopher's Stone , The Lord of the Rings: The Fellowship of the Ring , and Monsters, Inc. The highest-grossing non-English film was Studio Ghibli 's anime Spirited Away (Japanese), the 15th highest-grossing film of the year. The inaugural entries in the Harry Potter and Lord of the Rings film franchises brought fantasy into mainstream culture, popularizing young adult novels and catering to fandom communities. In music, 3.2 billion units were sold with a value of US$33.7 billion. DVD-Audio and Super Audio CD rose to prominence, with approximately 600 titles available in these formats. Portable music grew in popularity after Apple released the iTunes media library on January 9 and the first iPod music player device on October 23. The music sharing program Napster ended its services after it was accused of facilitating music piracy , but it was replaced by other programs such as FastTrack . : 177 Worldwide, the best-selling albums were Hybrid Theory (2000) by Linkin Park , No Angel (1999) by Dido , and Survivor (2001) by Destiny's Child . The best-selling non-English album was Cieli di Toscana ( transl. Tuscan Skies ; 2001) by Italian tenor Andrea Bocelli , which topped the charts in the Netherlands and Sweden and was the 23rd best-selling album globally. Three major video game systems were released in 2001: the GameCube and the Game Boy Advance by Nintendo and the Xbox by Microsoft. Meanwhile, Sega ended its involvement in the market after the failure of the Dreamcast . : 181 The year 2001 is considered important in the video game industry, partly because of the release of many games recognized as classics. Many video games released in 2001 defined or redefined their respective genres, including hack and slash game Devil May Cry , first-person shooter game Halo: Combat Evolved , and open world action-adventure game Grand Theft Auto III , which is regarded as an industry-defining work. Many sports events were postponed in the final months of 2001 after the September 11 attacks, particularly in the United States. Other sports were postponed in the United Kingdom and Ireland because of foot-and-mouth disease. Throughout the year, Salt Lake City , Utah, prepared for the 2002 Winter Olympics , while Beijing was announced as the host of the 2008 Summer Olympics . : 316 Qualifications for the 2002 FIFA World Cup were the main football events in 2001. : 534 The world record for largest victory in an international football match was set by Australia in a 0–22 victory against Tonga on April 9. Australia set this record again with a 31–0 victory against American Samoa on April 11. The unbalanced nature of these matches prompted changes to the FIFA qualification process. In Europe, the UEFA Women's Cup began its first season, establishing a continent-wide women's league for association football under the UEFA . American tennis player Jennifer Capriati won both the Australian Open and the French Open for 2001. : 316 NASCAR driver Dale Earnhardt , described as the greatest driver in the sport's history, died in a crash during the 2001 Daytona 500 on February 18. : 316 In April, golf player Tiger Woods became the only player to achieve a " Tiger Slam " after winning the 2001 Masters Tournament , in which he consecutively won all four championship golf titles outside of a single calendar year. The " Thunder in Africa " boxing match ended in a major upset after Hasim Rahman defeated champion Lennox Lewis on April 22. Lewis would go on to win a rematch on November 11. : 536 In cricket, Australia's record-setting streak of sixteen Test victories in a row was broken by India. : 537New buildings constructed or opened in 2001 include the Bibliotheca Alexandrina in Alexandria , : 163 the Sendai Mediatheque in Sendai , the DG Bank building in Berlin , the SEG Apartment Tower [ de ] in Vienna , and Aurora Place in Sydney . : 164 Museums that opened in 2001 include the Jewish Museum Berlin designed by Daniel Libeskind , the National Museum of Australia designed by Howard Raggatt in Canberra , the Changi Chapel and Museum in Singapore, the Neue Galerie New York , and the Apartheid Museum in Johannesburg . : 233 Prominent renovations made in 2001 include the Queen Elizabeth II Great Court in the British Museum : 163 and the entrance wing of the Milwaukee Art Museum . : 164 Preservation efforts were also completed on the Leaning Tower of Pisa , and it reopened to the public on December 15 after 12 years of reconstruction. Damaged and destroyed buildings included the World Trade Center buildings which were destroyed in the September 11 attacks, : 527 and the Biblioteca Gallardo in El Salvador, which was destroyed in an earthquake. : 232The 49th Venice Biennale shifted from traditional paintings and sculptures in 2001, giving an increased focus to film and architectural sculpture. : 525 : 167 Among art sales, Avant-garde works sold well, with the highest earning being Gerhard Richter 's painting of candles, which sold for US$5.4 million. : 525 The fashion industry saw a decline that was exacerbated by the September 11 attacks. After the attacks and the subsequent war in Afghanistan, styles with military or otherwise violent iconography were phased out. : 219–220 Improvements in inkjet printing made high resolution photography more practical. Japanese photographer Hiroshi Sugimoto exhibited his photographs of wax statues of historical figures to provoke questions about the nature of artistic depiction. : 171 Several iconic works of photojournalism were produced during the September 11 attacks, including The Falling Man and Raising the Flag at Ground Zero . The Sphere was the only artwork to be recovered from the site, and the sculpture continued to be displayed in its damaged form as a memorial. The most popular exhibition in 2001 was artwork depicting Jacqueline Kennedy 's time as first lady of the United States , followed closely by an exhibition for Johannes Vermeer and the Delft School , both at the Metropolitan Museum of Art . Each saw over 500,000 visitors. : 525 Other exhibitions in 2001 were held in honor of visual artists such as Jacob Lawrence , Clyfford Still , Thomas Eakins , Dan Graham , Henri Rousseau , Paul Signac , Gustav Klimt , Marc Chagall , Raymond Hains , Johannes Vermeer , William Blake ; architects such as Ludwig Mies van der Rohe , Rudolph Schindler , and Frank Gehry ; and photographers such as Walker Evans and August Sander . : 168–170 2001 was the first year in which architecture exhibitions saw major success in the art world. : 525The highest-grossing films in 2001 were Harry Potter and the Philosopher's Stone , The Lord of the Rings: The Fellowship of the Ring , and Monsters, Inc. The highest-grossing non-English film was Studio Ghibli 's anime Spirited Away (Japanese), the 15th highest-grossing film of the year. The inaugural entries in the Harry Potter and Lord of the Rings film franchises brought fantasy into mainstream culture, popularizing young adult novels and catering to fandom communities. In music, 3.2 billion units were sold with a value of US$33.7 billion. DVD-Audio and Super Audio CD rose to prominence, with approximately 600 titles available in these formats. Portable music grew in popularity after Apple released the iTunes media library on January 9 and the first iPod music player device on October 23. The music sharing program Napster ended its services after it was accused of facilitating music piracy , but it was replaced by other programs such as FastTrack . : 177 Worldwide, the best-selling albums were Hybrid Theory (2000) by Linkin Park , No Angel (1999) by Dido , and Survivor (2001) by Destiny's Child . The best-selling non-English album was Cieli di Toscana ( transl. Tuscan Skies ; 2001) by Italian tenor Andrea Bocelli , which topped the charts in the Netherlands and Sweden and was the 23rd best-selling album globally. Three major video game systems were released in 2001: the GameCube and the Game Boy Advance by Nintendo and the Xbox by Microsoft. Meanwhile, Sega ended its involvement in the market after the failure of the Dreamcast . : 181 The year 2001 is considered important in the video game industry, partly because of the release of many games recognized as classics. Many video games released in 2001 defined or redefined their respective genres, including hack and slash game Devil May Cry , first-person shooter game Halo: Combat Evolved , and open world action-adventure game Grand Theft Auto III , which is regarded as an industry-defining work. Many sports events were postponed in the final months of 2001 after the September 11 attacks, particularly in the United States. Other sports were postponed in the United Kingdom and Ireland because of foot-and-mouth disease. Throughout the year, Salt Lake City , Utah, prepared for the 2002 Winter Olympics , while Beijing was announced as the host of the 2008 Summer Olympics . : 316 Qualifications for the 2002 FIFA World Cup were the main football events in 2001. : 534 The world record for largest victory in an international football match was set by Australia in a 0–22 victory against Tonga on April 9. Australia set this record again with a 31–0 victory against American Samoa on April 11. The unbalanced nature of these matches prompted changes to the FIFA qualification process. In Europe, the UEFA Women's Cup began its first season, establishing a continent-wide women's league for association football under the UEFA . American tennis player Jennifer Capriati won both the Australian Open and the French Open for 2001. : 316 NASCAR driver Dale Earnhardt , described as the greatest driver in the sport's history, died in a crash during the 2001 Daytona 500 on February 18. : 316 In April, golf player Tiger Woods became the only player to achieve a " Tiger Slam " after winning the 2001 Masters Tournament , in which he consecutively won all four championship golf titles outside of a single calendar year. The " Thunder in Africa " boxing match ended in a major upset after Hasim Rahman defeated champion Lennox Lewis on April 22. Lewis would go on to win a rematch on November 11. : 536 In cricket, Australia's record-setting streak of sixteen Test victories in a row was broken by India. : 537A minor economic decline took place among many developed economies in 2001. It was amplified by the dot-com crash , in which dot-com companies went out of business every day for much of the year due to an overvaluation of the tech industry. Further economic disruption occurred in the aftermath of the September 11 attacks. These factors gave the first major demonstration of globalization causing mutual downturn across nations rather than the more typical mutual growth. : 7 Global growth in 2001 was the lowest in a decade, though middle income countries such as those in Eastern Europe were able to sustain growth despite the global downturn. : 30 Unemployment and deflation became concerns across developed nations. : 3 The year also marked a decline in international trade by about 1.5%, which contrasted with the 11% increase in 2000. This was the first negative change in international trade since 1982. IT industries and the dot-com crash are attributed for the decline in trade. Economic crises took place in Argentina and in Turkey . : 16 The recession in Argentina negatively affected the economy throughout Latin America, : 37 and the years-long economic crisis reached its peak in December, causing widespread social unrest and the resignation of the President of Argentina. : 16 America Online ( AOL ), a U.S. online service provider, was at the apex of its popularity and purchased the media conglomerate Time Warner . The deal was announced on January 10, in the largest merger in history at that time. AOL would rapidly shrink thereafter, partly due to the decline of dial-up and rise of broadband , and the deal would fall apart before the end of the decade, which would be regarded as one of the world's greatest business failures. Major businesses that ended operations in 2001 included the American energy company Enron and the national airlines of Belgium and Switzerland ( Sabena and Swissair , respectively). : 189 The Enron scandal took place in October 2001 when, Enron was found to be committing fraud, bringing about the criminal conviction of several executives and causing the company to undergo the largest bankruptcy at that point in U.S. history. E-commerce declined in 2001, with the exception of eBay , which saw significant growth. : 1782001 was the second hottest year on record at the time, exceeded only by 1998 . The Intergovernmental Panel on Climate Change released its Third Assessment Report on July 12. : 213 It warned that climate change in the 21st century could cause decreases in crop yields and an increase in temperature-related ailments and deaths. Droughts occurred in Australia, Central America, Kenya, and the Middle East, the latter continuing from years prior. Hungary, Russia and Southeast Asia experienced significant rains, causing flooding. North Asia underwent a severe winter. La Niña , which had been ongoing since 1998, ended in the east Atlantic by April 2001. : 186 The Kyoto Protocol was weakened in March when President George W. Bush determined that the United States would relinquish its commitments to the agreement, but an effort to maintain the agreement in Europe was led by Germany. : 486–487 There was an environmental scare in Europe during an investigation into depleted uranium from the Kosovo War , but it was shown to pose no threat. : 485 The Stockholm Convention on Persistent Organic Pollutants , which restricted several organic pollutants, was signed on May 22 and 23. : 491 There were four earthquakes in 2001 that caused significant casualties. El Salvador was struck by two of them: a 7.6-magnitude earthquake on January 13 and a 6.6-magnitude earthquake on February 13, which resulted in the deaths of at least 944 and 315 people respectively. The Bhuj earthquake , a 7.7-magnitude earthquake in Gujarat , India, on January 26 killed between 13,805 and 20,023 people, and destroyed nearly 340,000 buildings. An 8.4-magnitude earthquake , then the strongest that had occurred globally since 1965 , killed at least 77 people in Peru on June 23. A 7.8-magnitude earthquake struck China with an epicenter near Kokoxili , close to the border between Qinghai and Xinjiang , on November 14, but it occurred in a sparsely populated mountainous region and there were no casualties. Sicily saw the eruption of Mount Etna , beginning on July 17 and continuing into the next month. : 185 The 2001 Atlantic hurricane season was slightly more active than normal, including 15 tropical storms and hurricanes. The deadliest storms were Tropical Storm Allison in June, Hurricane Iris in October, and Hurricane Michelle in November. All three of these storms had their names retired by the World Meteorological Organization . Tropical Storm Allison was the deadliest tropical storm to hit the United States without reaching hurricane strength. The 2001 Pacific typhoon season was slightly larger than average, including 28 tropical storms, 20 typhoons, and 11 intense typhoons. The most powerful storms were Typhoon Podul in October and Typhoon Faxai in December. The World Health Organization (WHO) began a five-year program to reduce road injury fatalities following a warning of the problem's severity by the Red Cross the previous year. The WHO's Commission on Macroeconomics and Health released a report in 2001 detailing how spending by developed nations could protect health in developing nations. New drugs developed in 2001 include imatinib to treat cancer, and nateglinide to treat diabetes. : 224 2001 saw the first self-contained artificial heart implanted in a patient. : 25 Outbreaks of cholera occurred in Chad, India, Pakistan, Tanzania, South Africa, and throughout Western Africa; outbreaks of yellow fever took place in Brazil, Guinea, Ivory Coast, Liberia, and Peru; and outbreaks of meningococcal disease occurred in the African meningitis belt as well as Angola, the Democratic Republic of the Congo, and Ethiopia. Other major disease outbreaks included Crimean–Congo hemorrhagic fever in Kosovo and Pakistan, measles in India and South Korea, Legionnaires' disease in Spain and Norway, dengue fever in Venezuela, and plague in Zambia. : 223 Spain's outbreak of Legionnaires' disease was the largest ever recorded, with 449 confirmed cases and more than 800 suspected ones. An ebola outbreak continued from 2000 in Uganda until the final case was diagnosed on January 16. Another outbreak occurred in Gabon and the Republic of the Congo in October, which continued until July 2002. An outbreak of foot-and-mouth disease occurred among livestock in the United Kingdom in 2001, resulting in millions of farm animals being slaughtered to prevent spread. : 153–155 Approximately 400,000 people in New York City were exposed to air pollution by carcinogens and other harmful particles such as asbestos and metals as a result of the September 11 attacks , and many would go on to suffer chronic illness as a result of exposure. A series of anthrax attacks against American government and media figures in October further spurred precautions against bioterrorism. : 222Freedom House recognized 63% of national governments as electoral democracies by the end of 2001, with the Gambia and Mauritania being recognized as democracies following peaceful transfers of power. Peru also saw a significant expansion of civil rights after emerging from the authoritarian rule of Alberto Fujimori . Argentina, Liberia, Trinidad and Tobago, and Zimbabwe underwent significant democratic backsliding in 2001, with Liberia and Zimbabwe recognized as authoritarian governments by the end of the year. 64.65% of the world's population lived in countries that generally respected human rights, while 35.35% lived in countries that denied political rights and civil liberties. Islamic terrorism became the predominant global political concern amidst the September 11 attacks and the War on Terror. Islamic extremism was identified as a major threat to democracy and human rights, both in the Muslim world through the implementation of Islamism and in the rest of the world through terrorism. [ undue weight? – discuss ] Racial discrimination , the ability to prosecute human rights violators, the number of refugees, and the problems of economic disadvantage were among the global human rights concerns that were given the most attention in 2001. : 312 The Islamic State of Afghanistan was the de jure government of Afghanistan in 2001, but for several years it had operated as a government in exile while the Taliban-led Islamic Emirate of Afghanistan held de facto control over most of the country. The Islamic State of Afghanistan was restored to power following the invasion of Afghanistan with the appointment of president Hamid Karzai on December 22. : 43 Joseph Kabila became president of the Democratic Republic of the Congo following the assassination of his father, President. Laurent-Désiré Kabila . : 77 President Abdurrahman Wahid of Indonesia was removed from office after thousands of protesters stormed the parliament building, and he was replaced by Vice President Megawati Sukarnoputri , daughter of former president Sukarno . : 77 The Second EDSA Revolution took place in the Philippines in January when President Joseph Estrada resigned amid an impeachment , and he was succeeded by Vice President Gloria Macapagal Arroyo . : 77 The Argentine great depression escalated with rioting in December, prompting President Fernando de la Rúa to resign on December 20 and the fall of the interim government soon after. : 16 Kosovo and East Timor both held elections for the first time in 2001 as they sought independence. : 18 Other changes in leadership included the inauguration of George W. Bush as President of the United States , the election of Alejandro Toledo as President of Peru , : 16 the selection of Junichiro Koizumi as Prime Minister of Japan , : 19 and the election of Ariel Sharon as Prime Minister of Israel . Other leaders saw reconfirmation, including the reelection of Mohammad Khatami as President of Iran and the victory of the United Kingdom's Labour Party led by Tony Blair in the 2001 election . : 77 In response to the September 11 attacks, the United States passed the controversial Patriot Act that granted the U.S. government significant surveillance powers. Ghana underwent its first peaceful transfer of power since 1979 when John Kufuor was sworn in as President of Ghana on January 7. The Netherlands became the first modern country to legalize same-sex marriage on April 1. The royal family of Nepal was killed on June 1 by Crown Prince Dipendra , who became king upon his father's death. Dipendra fell into a coma after shooting himself, and he died days later. He in turn was succeeded by his uncle Gyanendra . : 72–73 The Constitution of the Comoros was amended on December 24, creating a federal government with a rotating presidency and granting increased autonomy to the three island administrations. Two major regional organizations were announced in 2001. The African Union was established on May 26 as a pan-African forum to promote unity between African countries, including cooperation in economic and security issues, and would replace the Organisation of African Unity in 2002. The Shanghai Cooperation Organisation was announced on June 15 to facilitate political and economic cooperation between Asian countries. Three countries joined the World Trade Organization (WTO) in 2001: Lithuania on May 31, Moldova on July 26, and China on December 11. The WTO began the Doha Development Round in November to negotiate lower trade barriers between countries and integrate developing nations into the global economy. : 18 The World Conference against Racism 2001 began on August 31, in Durban , South Africa, under the auspices of the United Nations . Israel and the United States withdrew from the conference on September 3 over objections to a draft resolution document equating Zionism with racism and singling out the Jewish state for war crimes. The Aarhus Convention took effect on October 30, establishing the right to environmental information and environmental justice for European and Central Asian countries. The 27th G8 summit was marred by anti-globalization protests in Genoa , Italy. Massive demonstrations, drawing an estimated 200,000 people, were held against the meeting. One demonstrator, Carlo Giuliani , was killed by a policeman, and several others were injured. : 76 [ failed verification ] The September 11 attacks demonstrated a need for international law to address terrorism and other non-state actors, and a push by UN Secretary General Kofi Annan in November saw progress in multiple international treaties. : 491 The Convention on Cybercrime , the first international treaty to address cybercrime , was signed on November 23. Diplomatic disputes in 2001 included a diplomatic incident when an American spy plane and a Chinese fighter plane collided over the South China Sea, : 70–71 and a dispute between Japan and North Korea when the North Korean leader's son, Kim Jong-nam , attempted to sneak into Tokyo Disneyland . : 76 Achievement tests and stricter penalties against delinquent students became controversial educational practices in several countries. : 206 Belgium set precedent when the government prosecuted crimes of the Rwandan genocide , invoking a 1993 law that gave Belgian courts jurisdiction over Geneva Conventions violations that take place anywhere in the world. : 226 In another first for international law, the International Criminal Tribunal for the former Yugoslavia determined that wartime sexual violence was a war crime. : 374 President Slobodan Milošević of Serbia (1997–2000) was arrested on April 1 for his role in the Srebrenica massacre and other crimes against humanity committed during the Bosnian War . He was the first head of state to see trial for war crimes in this manner. : 230 The tribunal also prosecuted general Radislav Krstić , bringing its first conviction for genocide. : 18 The International Court of Justice heard two new cases in 2001: Liechtenstein challenged Germany's claim that Lichtenstein property had been seized from Germany during World War II, and Nicaragua brought a challenge against Colombia regarding maritime borders. It delivered judgement in a 1991 case of a territorial dispute between Bahrain and Qatar, and it ruled in a German challenge against the United States that the court's own provisional orders are binding. : 492The Islamic State of Afghanistan was the de jure government of Afghanistan in 2001, but for several years it had operated as a government in exile while the Taliban-led Islamic Emirate of Afghanistan held de facto control over most of the country. The Islamic State of Afghanistan was restored to power following the invasion of Afghanistan with the appointment of president Hamid Karzai on December 22. : 43 Joseph Kabila became president of the Democratic Republic of the Congo following the assassination of his father, President. Laurent-Désiré Kabila . : 77 President Abdurrahman Wahid of Indonesia was removed from office after thousands of protesters stormed the parliament building, and he was replaced by Vice President Megawati Sukarnoputri , daughter of former president Sukarno . : 77 The Second EDSA Revolution took place in the Philippines in January when President Joseph Estrada resigned amid an impeachment , and he was succeeded by Vice President Gloria Macapagal Arroyo . : 77 The Argentine great depression escalated with rioting in December, prompting President Fernando de la Rúa to resign on December 20 and the fall of the interim government soon after. : 16 Kosovo and East Timor both held elections for the first time in 2001 as they sought independence. : 18 Other changes in leadership included the inauguration of George W. Bush as President of the United States , the election of Alejandro Toledo as President of Peru , : 16 the selection of Junichiro Koizumi as Prime Minister of Japan , : 19 and the election of Ariel Sharon as Prime Minister of Israel . Other leaders saw reconfirmation, including the reelection of Mohammad Khatami as President of Iran and the victory of the United Kingdom's Labour Party led by Tony Blair in the 2001 election . : 77 In response to the September 11 attacks, the United States passed the controversial Patriot Act that granted the U.S. government significant surveillance powers. Ghana underwent its first peaceful transfer of power since 1979 when John Kufuor was sworn in as President of Ghana on January 7. The Netherlands became the first modern country to legalize same-sex marriage on April 1. The royal family of Nepal was killed on June 1 by Crown Prince Dipendra , who became king upon his father's death. Dipendra fell into a coma after shooting himself, and he died days later. He in turn was succeeded by his uncle Gyanendra . : 72–73 The Constitution of the Comoros was amended on December 24, creating a federal government with a rotating presidency and granting increased autonomy to the three island administrations. Two major regional organizations were announced in 2001. The African Union was established on May 26 as a pan-African forum to promote unity between African countries, including cooperation in economic and security issues, and would replace the Organisation of African Unity in 2002. The Shanghai Cooperation Organisation was announced on June 15 to facilitate political and economic cooperation between Asian countries. Three countries joined the World Trade Organization (WTO) in 2001: Lithuania on May 31, Moldova on July 26, and China on December 11. The WTO began the Doha Development Round in November to negotiate lower trade barriers between countries and integrate developing nations into the global economy. : 18 The World Conference against Racism 2001 began on August 31, in Durban , South Africa, under the auspices of the United Nations . Israel and the United States withdrew from the conference on September 3 over objections to a draft resolution document equating Zionism with racism and singling out the Jewish state for war crimes. The Aarhus Convention took effect on October 30, establishing the right to environmental information and environmental justice for European and Central Asian countries. The 27th G8 summit was marred by anti-globalization protests in Genoa , Italy. Massive demonstrations, drawing an estimated 200,000 people, were held against the meeting. One demonstrator, Carlo Giuliani , was killed by a policeman, and several others were injured. : 76 [ failed verification ] The September 11 attacks demonstrated a need for international law to address terrorism and other non-state actors, and a push by UN Secretary General Kofi Annan in November saw progress in multiple international treaties. : 491 The Convention on Cybercrime , the first international treaty to address cybercrime , was signed on November 23. Diplomatic disputes in 2001 included a diplomatic incident when an American spy plane and a Chinese fighter plane collided over the South China Sea, : 70–71 and a dispute between Japan and North Korea when the North Korean leader's son, Kim Jong-nam , attempted to sneak into Tokyo Disneyland . : 76 Achievement tests and stricter penalties against delinquent students became controversial educational practices in several countries. : 206Belgium set precedent when the government prosecuted crimes of the Rwandan genocide , invoking a 1993 law that gave Belgian courts jurisdiction over Geneva Conventions violations that take place anywhere in the world. : 226 In another first for international law, the International Criminal Tribunal for the former Yugoslavia determined that wartime sexual violence was a war crime. : 374 President Slobodan Milošević of Serbia (1997–2000) was arrested on April 1 for his role in the Srebrenica massacre and other crimes against humanity committed during the Bosnian War . He was the first head of state to see trial for war crimes in this manner. : 230 The tribunal also prosecuted general Radislav Krstić , bringing its first conviction for genocide. : 18 The International Court of Justice heard two new cases in 2001: Liechtenstein challenged Germany's claim that Lichtenstein property had been seized from Germany during World War II, and Nicaragua brought a challenge against Colombia regarding maritime borders. It delivered judgement in a 1991 case of a territorial dispute between Bahrain and Qatar, and it ruled in a German challenge against the United States that the court's own provisional orders are binding. : 492The religiously motivated September 11 attacks came to dominate global discourse about religion in 2001. : 300 Following the attacks, both religious tolerance and religious intolerance came to the fore, with an increase in Islamophobia , particularly in the United States and Europe. The imposition of religious law became a major subject of debate, particularly in Afghanistan, where the perpetrators of the attacks were protected by the fundamentalist Taliban, as well as Nigeria, where conflict between Christians and Muslims escalated amid the implementation of Islamic law. : 300 Prior to the attacks, the Taliban had incited a different religious controversy by destroying the Buddhas of Bamiyan despite the international community's pleas. : 76 Another religious conflict took place in Khartoum , Sudan, when Christians were forcibly expelled from the Anglican cathedral during Easter services. : 470 Pope John Paul II made trips throughout 2001 to preach for good relations with other religions: he became the first pope to visit a mosque in Syria to build relations with Muslims, and he visited Greece to build relations with Orthodox Christians. Relations between Catholicism and Judaism were strained following a dispute over the release of Holocaust records held by the Vatican. : 300–301 The Pope named 37 cardinals on January 21, bringing the total number to 128. : 469 The Catholic Church also began investigations of sexual abuse cases among its priests in 2001, with 3,000 cases being considered over the following decade. The subject of women's ordination was also a subject of debate within the Catholic Church. : 470 The duodecennial Hindu pilgrimage and festival Kumbh Mela was held for 42 days in January and February 2001. : 308 A 50-square-mile (130 km 2 ) tent city was created within Allahabad to support the festival. : 471 The Sultan Qaboos Grand Mosque in Oman was completed in May. At the time, its chandelier was the largest in the world. Jediism became a social phenomenon in 2001 after a movement to self-report as Jedi caused it to become the fourth largest religion in the United Kingdom and the second largest religion in New Zealand. Several anthropological and archaeological developments were made in 2001, including the extraction of mtDNA from prehistoric skeletons : 158 and the discovery of an arrowhead lodged in the shoulder of Ötzi , a 5,300-year-old mummy, after a CT scan was performed on him. : 128 Newly described hominids included Sahelanthropus and Ardipithecus , while two additional hominids, Kenyanthropus and Orrorin , were proposed. : 158–159 January saw the extraction of DNA from a 60,000-year-old skeleton, the oldest human DNA to be studied to that point. : 480 In October, the discovery of a prehistoric Sarcosuchus skeleton was announced after digging began the previous year. : 125 Archaeological discoveries include rock art in Andros , 40,000-year-old tools in Mamontovaya Kurya , terracotta citizens in a pit adjacent to the Terracotta Army , a walled city at Dholavira , and a 2,900-year-old sweat lodge in Cuello . : 160–162 Two different groups, the Human Genome Project and Celera Genomics , published the first maps of the human genome on February 15 and 16, respectively. Human cloning was a controversial subject in 2001, and opponents called for bans on human cloning internationally. : 477–478 : 215 Other developments in genetics included a completed sequencing of the oryza sativa genome and an experiment saw the successful creation of tomatoes genetically modified to survive in saltwater. : 237 The pygmy three-toed sloth was among the animals first described in 2001. Birds discovered include the Mishana tyrannulet , the Chapada flycatcher , the Vanuatu petrel , and the chestnut-eared laughingthrush . : 215 The Ruizia parviflora tree was rediscovered on Mauritius when it was thought extinct since 1863. : 238 Conversely, the 1993 discovery of pseudonovibos spiralis was determined in February 2001 to be unfounded. The discovery of the Lost City Hydrothermal Field on the Atlantis Massif was formally announced in 2001. : 183 The phenomenon of neutrino oscillation was confirmed in 2001, while the 1999 discovery of element 118 was retracted. : 263 The University of the Arctic was founded in 2001 as a joint project between several northern countries. : 210 The computer industry saw major decline during the recession in 2001. : 175 Apple Computer Inc. released the Mac OS X operating system for Mac computers on March 24, : 176 and it discontinued the Power Mac G4 Cube . : 176 3G wireless technology first became available on October 1 when it was adopted by Japanese telecommunications company NTT Docomo with its Freedom of Mobile Multimedia Access service. : 182 Microsoft released the Windows XP operating system to retail on October 25. : 175 The most powerful supercomputer as of 2001 was designed by IBM for the Lawrence Livermore National Laboratory in the United States. Several malware scares took place in 2001, including the Code Red , Nimda , and Sircam worms. : 180 There were only 57 successful orbital spaceflights in 2001, the fewest since 1963. Eight of these launches were crewed missions. Two failed spaceflights also took place. The NEAR Shoemaker made the first successful landing of a spacecraft on an asteroid on February 12, and the Destiny module was connected to the International Space Station the same month. : 474–475 The Russian Mir space station was deorbited and destroyed on March 23, landing in the Pacific Ocean. : 126 The 2001 Mars Odyssey orbiter was launched on April 7 and arrived at Mars on October 24. American entrepreneur Dennis Tito became the first space tourist on April 28 aboard the Russian Soyuz TM-32 . 28978 Ixion was discovered on May 22. The Genesis probe was launched on August 8 to collect solar wind samples. Deep Space 1 carried out a flyby of Comet Borrelly on September 22, and Galileo carried out a flyby of Io on October 15. An atmosphere was discovered on an exoplanet for the first time on November 27. Air travel in the United States and worldwide was heavily affected by the September 11 attacks. Commercial flights in the United States were grounded for three days, and air travel then became subject to significantly increased security measures. Incheon International Airport opened in Incheon on March 22, and the TGV Mediterranee railway opened in France. : 166 The K-141 Kursk nuclear submarine was lifted from the Barents Sea after the Kursk submarine disaster of the previous year. : 74–75 The Segway , a self-balancing personal transporter invented by Dean Kamen , was unveiled on December 3 after months of public speculation and media hype, on the ABC News morning program Good Morning America . The reveal that it was a self-balancing transporter was seen as a disappointment. : 477The computer industry saw major decline during the recession in 2001. : 175 Apple Computer Inc. released the Mac OS X operating system for Mac computers on March 24, : 176 and it discontinued the Power Mac G4 Cube . : 176 3G wireless technology first became available on October 1 when it was adopted by Japanese telecommunications company NTT Docomo with its Freedom of Mobile Multimedia Access service. : 182 Microsoft released the Windows XP operating system to retail on October 25. : 175 The most powerful supercomputer as of 2001 was designed by IBM for the Lawrence Livermore National Laboratory in the United States. Several malware scares took place in 2001, including the Code Red , Nimda , and Sircam worms. : 180 There were only 57 successful orbital spaceflights in 2001, the fewest since 1963. Eight of these launches were crewed missions. Two failed spaceflights also took place. The NEAR Shoemaker made the first successful landing of a spacecraft on an asteroid on February 12, and the Destiny module was connected to the International Space Station the same month. : 474–475 The Russian Mir space station was deorbited and destroyed on March 23, landing in the Pacific Ocean. : 126 The 2001 Mars Odyssey orbiter was launched on April 7 and arrived at Mars on October 24. American entrepreneur Dennis Tito became the first space tourist on April 28 aboard the Russian Soyuz TM-32 . 28978 Ixion was discovered on May 22. The Genesis probe was launched on August 8 to collect solar wind samples. Deep Space 1 carried out a flyby of Comet Borrelly on September 22, and Galileo carried out a flyby of Io on October 15. An atmosphere was discovered on an exoplanet for the first time on November 27. Air travel in the United States and worldwide was heavily affected by the September 11 attacks. Commercial flights in the United States were grounded for three days, and air travel then became subject to significantly increased security measures. Incheon International Airport opened in Incheon on March 22, and the TGV Mediterranee railway opened in France. : 166 The K-141 Kursk nuclear submarine was lifted from the Barents Sea after the Kursk submarine disaster of the previous year. : 74–75 The Segway , a self-balancing personal transporter invented by Dean Kamen , was unveiled on December 3 after months of public speculation and media hype, on the ABC News morning program Good Morning America . The reveal that it was a self-balancing transporter was seen as a disappointment. : 477

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Crimean-Congo haemorrhagic fever

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2017 Uganda Marburg virus outbreak

The 2017 Uganda Marburg virus outbreak was confirmed by the World Health Organization (WHO) on 20 October 2017 after there had been an initial fatality due to the virus. The Ugandan Ministry of Health indicated that an individual had died of the virus on 19 October; the following day, 20 October, WHO released a press statement regarding the matter. The eastern part of the country is the affected area where the cases have occurred. On 22 October, it was reported that 55 individuals were under surveillance for the virus. On 25 October, the number of individuals rose to 155 in terms of contact tracing According to the Centers for Disease Control and Prevention (CDC), the Marburg virus was first recognised in 1967. In terms of diagnosis the presentation is similar to malaria or typhoid fever and therefore not easy to identify (diagnose). The Marburg virus is considered a filovirus , which is the same as the Ebola virus in terms of viral classification. According to Mehedi, et al. macrophages , monocytes , and dendritic cells , are what the virus attacks due to their importance in the human bodies normal mechanism According to the World Health Organization there is currently no treatment for the disease. As of 11 November 2017, according to the Ministry of Health no new cases have been reported to this point the report originates from Kampala . On 8 December the World Health Organization declared the end to the outbreak in the country of Uganda due to two 21-day quarantine periods The table lists a subset of the Marburg virus disease outbreaks, which have occurred specifically in Uganda:The table lists a subset of the Marburg virus disease outbreaks, which have occurred specifically in Uganda:

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Chikungunya

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Chikungunya

Chikungunya is an infection caused by the Chikungunya virus ( CHIKV ). The disease was first identified in 1952 in Tanzania and named based on the Kimakonde words for "to become contorted". Symptoms include fever and joint pain . These typically occur two to twelve days after exposure. Other symptoms may include headache , muscle pain , joint swelling , and a rash . Symptoms usually improve within a week; however, occasionally the joint pain may last for months or years. The risk of death is around 1 in 1,000. The very young, old, and those with other health problems are at risk of more severe disease. The virus is spread between people by two types of mosquitos : Aedes albopictus and Aedes aegypti . They mainly bite during the day. The virus may circulate within a number of animals including birds and rodents . Diagnosis is by either testing the blood for viral RNA or antibodies to the virus. The symptoms can be mistaken for those of dengue fever and Zika fever . It is believed most people become immune after a single infection. The best means of prevention are overall mosquito control and the avoidance of bites in areas where the disease is common. This may be partly achieved by decreasing mosquitos' access to water and by the use of insect repellent and mosquito nets . In November 2023 the USFDA approved an adults-only vaccine ( Ixchiq ) for prevention of the disease. Once infected and symptomatic, recommendations to patients should include rest, fluids, and medications to help with fever and joint pain. In 2014, more than a million suspected cases occurred globally. While the disease is endemic in Africa and Asia, outbreaks have been reported in Europe and the Americas since the 2000s; in 2014, an outbreak was reported in Florida in the continental United States , but as of 2016 there were no further locally-acquired cases. Around 85% of people infected with Chikungunya virus experience symptoms, typically beginning with a sudden high fever above 39 °C (102 °F) . The fever is soon followed by severe muscle and joint pain . Pain usually affects multiple joints in the arms and legs, and is symmetric – i.e. if one elbow is affected, the other is as well. People with Chikungunya also frequently experience headache , back pain, nausea , and fatigue . Around half of those affected develop a rash , with reddening and sometimes small bumps on the palms, foot soles, torso, and face. For some, the rash remains constrained to a small part of the body; for others, the rash can be extensive, covering more than 90% of the skin. Some people experience gastrointestinal issues, with abdominal pain and vomiting. Others experience eye problems, namely sensitivity to light , conjunctivitis , and pain behind the eye. This first set of symptoms – called the "acute phase" of Chikungunya – lasts around a week, after which most symptoms resolve on their own. Many people continue to have symptoms after the "acute phase" resolves, termed the "post-acute phase" for symptoms lasting three weeks to three months, and the "chronic stage" for symptoms lasting longer than three months. In both cases, the lasting symptoms tend to be joint pains: arthritis , tenosynovitis , and/or bursitis . If the affected person had pre-existing joint issues, these tend to worsen. Overuse of a joint can result in painful swelling, stiffness, nerve damage, and neuropathic pain . Typically the joint pain improves with time; however, the chronic stage can last anywhere from a few months to several years. Joint pain is reported in 87–98% of cases, and nearly always occurs in more than one joint, though joint swelling is uncommon. Typically the affected joints are located in both arms and legs. Joints are more likely to be affected if they have previously been damaged by disorders such as arthritis . Pain most commonly occurs in peripheral joints, such as the wrists, ankles, and joints of the hands and feet as well as some of the larger joints, typically the shoulders, elbows and knees. Pain may also occur in the muscles or ligaments . In more than half of cases, normal activity is limited by significant fatigue and pain. Infrequently, inflammation of the eyes may occur in the form of iridocyclitis , or uveitis , and retinal lesions may occur. Temporary damage to the liver may occur. People with Chikungunya occasionally develop neurologic disorders, most frequently swelling or degeneration of the brain, inflammation or degeneration of the myelin sheaths around neurons, Guillain–Barré syndrome , acute disseminated encephalomyelitis , hypotonia (in newborns), and issues with visual processing. In particularly rare cases, people may develop behavioral changes, seizures, irritation of the cerebellum or meninges , oculomotor nerve palsy , or paralysis of the eye muscles . Newborns are susceptible to particularly severe effects of Chikungunya infection. Signs of infection typically begin with fever, rash, and swelling in the extremities. Around half of newborns have a mild case of the disease that resolves on its own; the other half have severe disease with inflammation of the brain and seizures . In severe cases, affected newborns may also have issues with bleeding and bloodflow, and problems with heart function. In addition to newborns, the elderly, and those with diabetes , heart disease , liver and kidney diseases, and human immunodeficiency virus infection tend to have more severe cases of Chikungunya. Around 1 to 5 in 1,000 people with symptomatic Chikungunya die of the disease. Chikungunya virus (CHIKV), is a member of the genus Alphavirus , and family Togaviridae . It was first isolated in 1953 in Tanzania and is an RNA virus with a positive-sense single-stranded genome of about 11.6kb. It is a member of the Semliki Forest virus complex and is closely related to Ross River virus , O'nyong'nyong virus , and Semliki Forest virus . Because it is transmitted by arthropods , namely mosquitoes, it can also be referred to as an arbovirus ( ar thropod- bo rne virus). In the United States, it is classified as a category B priority pathogen , and work requires biosafety level III precautions. Chikungunya is generally transmitted from mosquitoes to humans. Less common modes of transmission include vertical transmission , which is transmission from mother to child during pregnancy or at birth. Transmission via infected blood products and through organ donation is also theoretically possible during times of outbreak, though no cases have yet been documented. The incubation period ranges from one to twelve days, and is most typically three to seven. Chikungunya is related to mosquitoes , their environments, and human behavior. The adaptation of mosquitoes to the changing climate of North Africa around 5,000 years ago made them seek out environments where humans stored water. Human habitation and the mosquitoes' environments were then very closely connected. During periods of epidemics humans are the reservoir of the virus. Because high amounts of virus are present in the blood in the beginning of acute infection, the virus can be spread from a viremic human to a mosquito, and back to a human. During other times, monkeys, birds and other vertebrates have served as reservoirs. Three genotypes of this virus have been described, each with a distinct genotype and antigenic character: West African, East/Central/South African, and Asian genotypes. The Asian lineage originated in 1952 and has subsequently split into two lineages – India (Indian Ocean Lineage) and South East Asian clades. This virus was first reported in the Americas in 2014. Phylogenetic investigations have shown that there are two strains in Brazil – the Asian and East/Central/South African types – and that the Asian strain arrived in the Caribbean (most likely from Oceania) in about March 2013. The rate of molecular evolution was estimated to have a mean rate of 5 × 10 −4 substitutions per site per year (95% higher probability density 2.9–7.9 × 10 −4 ). Chikungunya is spread through bites from Aedes mosquitoes, and the species A. aegypti was identified as the most common vector, though the virus has recently been associated with many other species, including A. albopictus . Research by the Pasteur Institute in Paris has suggested Chikungunya virus strains in the 2005-2006 Reunion Island outbreak incurred a mutation that facilitated transmission by the Asian tiger mosquito ( A. albopictus ). Other species potentially able to transmit Chikungunya virus include Ae. furcifer-taylori , Ae. africanus , and Ae. luteocephalus . Chikungunya virus (CHIKV), is a member of the genus Alphavirus , and family Togaviridae . It was first isolated in 1953 in Tanzania and is an RNA virus with a positive-sense single-stranded genome of about 11.6kb. It is a member of the Semliki Forest virus complex and is closely related to Ross River virus , O'nyong'nyong virus , and Semliki Forest virus . Because it is transmitted by arthropods , namely mosquitoes, it can also be referred to as an arbovirus ( ar thropod- bo rne virus). In the United States, it is classified as a category B priority pathogen , and work requires biosafety level III precautions. Chikungunya is generally transmitted from mosquitoes to humans. Less common modes of transmission include vertical transmission , which is transmission from mother to child during pregnancy or at birth. Transmission via infected blood products and through organ donation is also theoretically possible during times of outbreak, though no cases have yet been documented. The incubation period ranges from one to twelve days, and is most typically three to seven. Chikungunya is related to mosquitoes , their environments, and human behavior. The adaptation of mosquitoes to the changing climate of North Africa around 5,000 years ago made them seek out environments where humans stored water. Human habitation and the mosquitoes' environments were then very closely connected. During periods of epidemics humans are the reservoir of the virus. Because high amounts of virus are present in the blood in the beginning of acute infection, the virus can be spread from a viremic human to a mosquito, and back to a human. During other times, monkeys, birds and other vertebrates have served as reservoirs. Three genotypes of this virus have been described, each with a distinct genotype and antigenic character: West African, East/Central/South African, and Asian genotypes. The Asian lineage originated in 1952 and has subsequently split into two lineages – India (Indian Ocean Lineage) and South East Asian clades. This virus was first reported in the Americas in 2014. Phylogenetic investigations have shown that there are two strains in Brazil – the Asian and East/Central/South African types – and that the Asian strain arrived in the Caribbean (most likely from Oceania) in about March 2013. The rate of molecular evolution was estimated to have a mean rate of 5 × 10 −4 substitutions per site per year (95% higher probability density 2.9–7.9 × 10 −4 ). Chikungunya is spread through bites from Aedes mosquitoes, and the species A. aegypti was identified as the most common vector, though the virus has recently been associated with many other species, including A. albopictus . Research by the Pasteur Institute in Paris has suggested Chikungunya virus strains in the 2005-2006 Reunion Island outbreak incurred a mutation that facilitated transmission by the Asian tiger mosquito ( A. albopictus ). Other species potentially able to transmit Chikungunya virus include Ae. furcifer-taylori , Ae. africanus , and Ae. luteocephalus . Chikungunya virus is passed to humans when a bite from an infected mosquito breaks the skin and introduces the virus into the body. The pathogenesis of chikungunya infection in humans is still poorly understood, despite recent outbreaks. It appears that in vitro , Chikungunya virus is able to replicate in human epithelial and endothelial cells , primary fibroblasts , and monocyte-derived macrophages . Viral replication is highly cytopathic , but susceptible to type-I and -II interferon . In vivo , in studies using living cells, chikungunya virus appears to replicate in fibroblasts, skeletal muscle progenitor cells, and myofibers. The type-1 interferon response seems to play an important role in the host's response to chikungunya infection. Upon infection with chikungunya, the host's fibroblasts produce type-1 alpha and beta interferon ( IFN-α and IFN-β ). In mouse studies, deficiencies in INF-1 in mice exposed to the virus cause increased morbidity and mortality. The chikungunya-specific upstream components of the type-1 interferon pathway involved in the host's response to chikungunya infection are still unknown. Nonetheless, mouse studies suggest that IPS-1 is an important factor, and that IRF3 and IRF7 are important in an age-dependent manner. Mouse studies also suggest that chikungunya evades host defenses and counters the type-I interferon response by producing NS2, a nonstructural protein that degrades RBP1 and turns off the host cell's ability to transcribe DNA. NS2 interferes with the JAK-STAT signaling pathway and prevents STAT from becoming phosphorylated . In the acute phase of chikungunya, the virus is typically present in the areas where symptoms present, specifically skeletal muscles, and joints . In the chronic phase, it is suggested that viral persistence (the inability of the body to entirely rid itself of the virus), lack of clearance of the antigen , or both, contribute to joint pain. The inflammation response during both the acute and chronic phase of the disease results in part from interactions between the virus and monocytes and macrophages. Chikungunya virus disease in humans is associated with elevated serum levels of specific cytokines and chemokines . High levels of specific cytokines have been linked to more severe acute disease: interleukin-6 (IL-6), IL-1β , RANTES , monocyte chemoattractant protein 1 (MCP-1), monokine induced by gamma interferon (MIG), and interferon gamma-induced protein 10 (IP-10). Cytokines may also contribute to chronic Chikungunya virus disease, as persistent joint pain has been associated with elevated levels of IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF). In those with chronic symptoms, a mild elevation of C-reactive protein (CRP) has been observed, suggesting ongoing chronic inflammation. However, there is little evidence linking chronic Chikungunya virus disease and the development of autoimmunity . [ citation needed ] The virus consists of four nonstructural proteins and three structural proteins. The structural proteins are the capsid and two envelope glycoproteins: E1 and E2, which form heterodimeric spikes on the viron surface. E2 binds to cellular receptors in order to enter the host cell through receptor-mediated endocytosis . E1 contains a fusion peptide which, when exposed to the acidity of the endosome in eukaryotic cells , dissociates from E2 and initiates membrane fusion that allows the release of nucleocapsids into the host cytoplasm, promoting infection. The mature virion contains 240 heterodimeric spikes of E2/E1, which after release, bud on the surface of the infected cell, where they are released by exocytosis to infect other cells. The virus consists of four nonstructural proteins and three structural proteins. The structural proteins are the capsid and two envelope glycoproteins: E1 and E2, which form heterodimeric spikes on the viron surface. E2 binds to cellular receptors in order to enter the host cell through receptor-mediated endocytosis . E1 contains a fusion peptide which, when exposed to the acidity of the endosome in eukaryotic cells , dissociates from E2 and initiates membrane fusion that allows the release of nucleocapsids into the host cytoplasm, promoting infection. The mature virion contains 240 heterodimeric spikes of E2/E1, which after release, bud on the surface of the infected cell, where they are released by exocytosis to infect other cells. Chikungunya is diagnosed on the basis of clinical, epidemiological, and laboratory criteria. Clinically, acute onset of high fever and severe joint pain would lead to suspicion of chikungunya. Epidemiological criteria consist of whether the individual has traveled to or spent time in an area in which chikungunya is present within the last twelve days (i.e.) the potential incubation period). Laboratory criteria include a decreased lymphocyte count consistent with viremia . However a definitive laboratory diagnosis can be accomplished through viral isolation, RT-PCR, or serological diagnosis. The differential diagnosis may include other mosquito-borne diseases , such as dengue or malaria , or other infections such as influenza . Chronic recurrent polyarthralgia occurs in at least 20% of chikungunya patients one year after infection, whereas such symptoms are uncommon in dengue. Virus isolation provides the most definitive diagnosis, but takes one to two weeks for completion and must be carried out in biosafety level III laboratories . The technique involves exposing specific cell lines to samples from whole blood and identifying Chikungunya virus -specific responses. RT-PCR using nested primer pairs is used to amplify several chikungunya-specific genes from whole blood, generating thousands to millions of copies of the genes in order to identify them. RT-PCR can also be used to quantify the viral load in the blood. Using RT-PCR, diagnostic results can be available in one to two days. Serological diagnosis requires a larger amount of blood than the other methods, and uses an ELISA assay to measure chikungunya-specific IgM levels in the blood serum. One advantage offered by serological diagnosis is that serum IgM is detectable from 5 days to months after the onset of symptoms, but drawbacks are that results may require two to three days, and false positives can occur with infection due to other related viruses, such as o'nyong'nyong virus and Semliki Forest virus . Presently, there is no specific way to test for chronic signs and symptoms associated with Chikungunya fever although nonspecific laboratory findings such as C reactive protein and elevated cytokines can correlate with disease activity. Because no approved vaccine exists, the most effective means of prevention are protection against contact with the disease-carrying mosquitoes and controlling mosquito populations by limiting their habitat . Mosquito control focuses on eliminating the standing water where mosquitos lay eggs and develop as larva; if elimination of the standing water is not possible, insecticides or biological control agents can be added. Methods of protection against contact with mosquitos include using insect repellents with substances such as DEET , icaridin , PMD ( p-menthane-3,8-diol , a substance derived from the lemon eucalyptus tree), or ethyl butylacetylaminopropionate (IR3535). However, increasing insecticide resistance presents a challenge to chemical control methods. [ citation needed ] Wearing bite-proof long sleeves and trousers also offers protection, and garments can be treated with pyrethroids , a class of insecticides that often has repellent properties. Vaporized pyrethroids (for example in mosquito coils) are also insect repellents. As infected mosquitoes often feed and rest inside homes, securing screens on windows and doors will help to keep mosquitoes out of the house. In the case of the day-active A. aegypti and A. albopictus , however, this will have only a limited effect, since many contacts between the mosquitoes and humans occur outdoors. [ citation needed ] A Chikungunya vaccine is a vaccine intended to provide acquired immunity against the chikungunya virus . The most commonly reported side effects include headache, fatigue, muscle pain, joint pain, fever, nausea and tenderness at the injection site. A Chikungunya vaccine is a vaccine intended to provide acquired immunity against the chikungunya virus . The most commonly reported side effects include headache, fatigue, muscle pain, joint pain, fever, nausea and tenderness at the injection site. Currently, no specific treatment for chikungunya is available. Supportive care is recommended, and symptomatic treatment of fever and joint swelling includes the use of nonsteroidal anti-inflammatory drugs such as naproxen , non-aspirin analgesics such as paracetamol (acetaminophen) and fluids. Aspirin is not recommended due to the increased risk of bleeding. Despite anti-inflammatory effects, corticosteroids are not recommended during the acute phase of disease, as they may cause immunosuppression and worsen infection. Passive immunotherapy has potential benefit in treatment of chikungunya. Studies in animals using passive immunotherapy have been effective, and clinical studies using passive immunotherapy in those particularly vulnerable to severe infection are currently in progress. Passive immunotherapy involves administration of anti-CHIKV hyperimmune human intravenous antibodies (immunoglobulins) to those exposed to a high risk of chikungunya infection. No antiviral treatment for Chikungunya virus is currently available, though testing has shown several medications to be effective in vitro . In those who have more than two weeks of arthritis, ribavirin may be useful. The effect of chloroquine is not clear. It does not appear to help acute disease, but tentative evidence indicates it might help those with chronic arthritis. Steroids do not appear to be an effective treatment. NSAIDs and simple analgesics can be used to provide partial symptom relief in most cases. Methotrexate , a drug used in the treatment of rheumatoid arthritis , has been shown to have benefit in treating inflammatory polyarthritis resulting from chikungunya, though the drug mechanism for improving viral arthritis is unclear. In those who have more than two weeks of arthritis, ribavirin may be useful. The effect of chloroquine is not clear. It does not appear to help acute disease, but tentative evidence indicates it might help those with chronic arthritis. Steroids do not appear to be an effective treatment. NSAIDs and simple analgesics can be used to provide partial symptom relief in most cases. Methotrexate , a drug used in the treatment of rheumatoid arthritis , has been shown to have benefit in treating inflammatory polyarthritis resulting from chikungunya, though the drug mechanism for improving viral arthritis is unclear. The mortality rate of chikungunya is slightly less than 1 in 1000. Those over the age of 65, neonates, and those with underlying chronic medical problems are most likely to have severe complications. Neonates are vulnerable as it is possible to vertically transmit chikungunya from mother to infant during delivery, which results in high rates of morbidity, as infants lack fully developed immune systems . The likelihood of prolonged symptoms or chronic joint pain is increased with increased age and prior rheumatological disease. Historically, chikungunya has been present mostly in the developing world . The disease causes an estimated 3 million infections each year. Epidemics in the Indian Ocean, Pacific Islands, and in the Americas, continue to change the distribution of the disease. In Africa, chikungunya is spread by a sylvatic cycle in which the virus largely cycles between other non-human primates , small mammals, and mosquitos between human outbreaks. During outbreaks, due to the high concentration of virus in the blood of those in the acute phase of infection, the virus can circulate from humans to mosquitoes and back to humans. The transmission of the pathogen between humans and mosquitoes that exist in urban environments was established on multiple occasions from strains occurring on the eastern half of Africa in non-human primate hosts. This emergence and spread beyond Africa may have started as early as the 18th century. Currently, available data does not indicate whether the introduction of chikungunya into Asia occurred in the 19th century or more recently, but this epidemic Asian strain causes outbreaks in India and continues to circulate in Southeast Asia. In Africa, outbreaks were typically tied to heavy rainfall causing increased mosquito population. In recent outbreaks in urban centers, the virus has spread by circulating between humans and mosquitoes. Global rates of chikungunya infection are variable, depending on outbreaks. When chikungunya was first identified in 1952, it had a low-level circulation in West Africa, with infection rates linked to rainfall. Beginning in the 1960s, periodic outbreaks were documented in Asia and Africa. However, since 2005, following several decades of relative inactivity, chikungunya has re-emerged and caused large outbreaks in Africa, Asia, and the Americas. In India, for instance, chikungunya re-appeared following 32 years of absence of viral activity. Outbreaks have occurred in Europe, the Caribbean, and South America, areas in which chikungunya was not previously transmitted. Local transmission has also occurred in the United States and Australia, countries in which the virus was previously unknown. In 2005, an outbreak on the island of Réunion was the largest then documented, with an estimated 266,000 cases on an island with a population of approximately 770,000. In a 2006 outbreak, India reported 1.25 million suspected cases. Chikungunya was introduced to the Americas in 2013, first detected on the French island of Saint Martin , and for the next two years in the Americas, 1,118,763 suspected cases and 24,682 confirmed cases were reported by the PAHO . An analysis of the genetic code of Chikungunya virus suggests that the increased severity of the 2005–present outbreak may be due to a change in the genetic sequence which altered the E1 segment of the virus' viral coat protein, a variant called E1-A226V. This mutation potentially allows the virus to multiply more easily in mosquito cells. The change allows the virus to use the Asian tiger mosquito (an invasive species ) as a vector in addition to the more strictly tropical main vector, Aedes aegypti . Enhanced transmission of Chikungunya virus by A. albopictus could mean an increased risk for outbreaks in other areas where the Asian tiger mosquito is present. A albopictus is an invasive species which has spread through Europe, the Americas, the Caribbean, Africa and the Middle East. [ citation needed ] After the detection of zika virus in Brazil in April 2015, the first ever in the Western Hemisphere, it is now thought some chikungunya and dengue cases could in fact be zika virus cases or coinfections .The disease was first described by Marion Robinson and W.H.R. Lumsden in a pair of 1955 papers, following an outbreak in 1952 on the Makonde Plateau , along the border between Mozambique and Tanganyika (the mainland part of modern-day Tanzania ). Since then outbreaks have occurred occasionally in Africa, South Asia, and Southeast Asia; recent outbreaks have spread the disease over a wider range. [ citation needed ] The first recorded outbreak may have been in 1779. This is in agreement with the molecular genetics evidence that suggests it evolved around the year 1700. According to the original paper by Lumsden, the term 'chikungunya' is derived from the Makonde root verb kungunyala , meaning to dry up or become contorted. In concurrent research, Robinson [ citation needed ] glossed the Makonde term more specifically as "that which bends up". It is understood to refer to the contorted posture of people affected with the severe joint pain and arthritic symptoms associated with this disease. Subsequent authors apparently overlooked the references to the Makonde language and assumed the term to have been derived from Swahili , the lingua franca of the region. The erroneous attribution to Swahili has been repeated in numerous print sources. Erroneous spellings of the name of the disease are also in common use. [ citation needed ]Chikungunya is one of more than a dozen agents researched as a potential biological weapon . This disease is part of the group of neglected tropical diseases .

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Chikungunya

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Chikungunya vaccine

None A Chikungunya vaccine is a vaccine intended to provide acquired immunity against the chikungunya virus . The most commonly reported side effects include headache, fatigue, muscle pain, joint pain, fever, nausea and tenderness at the injection site. The first chikungunya vaccine was approved for medical use in the United States in November 2023. The chikungunya vaccine is indicated for the prevention of disease caused by chikungunya virus in individuals 18 years of age and older who are at high risk of exposure to the chikungunya virus. The safety of the chikungunya vaccine was evaluated in two clinical studies conducted in North America in which about 3,500 participants 18 years of age and older received a dose of the vaccine with one study including about 1,000 participants who received a placebo. The effectiveness of the chikungunya vaccine is based on immune response data from a clinical study conducted in the United States in individuals 18 years of age and older. In this study, the immune response of 266 participants who received the vaccine was compared to the immune response of 96 participants who received placebo. The level of antibody evaluated in study participants was based on a level shown to be protective in non-human primates that had received blood from people who had been vaccinated. Almost all vaccine study participants achieved this antibody level. The US Food and Drug Administration (FDA) granted the application for the chikungunya vaccine fast track , breakthrough therapy , and priority review designations. The FDA granted approval of Ixchiq to Valneva Austria GmbH. A phase-II vaccine trial used a live, attenuated virus , to develop viral resistance in 98% of those tested after 28 days and 85% still showed resistance after one year. However, 8% of people reported transient joint pain, and attenuation was found to be due to only two mutations in the E2 glycoprotein. Alternative vaccine strategies have been developed, and show efficacy in mouse models. In August 2014, researchers at the National Institute of Allergy and Infectious Diseases in the USA tested an experimental vaccine using virus-like particles (VLPs) instead of attenuated virus. All of the 25 people participating in this phase I trial developed strong immune responses. As of 2015, a phase II trial was planned, using 400 adults aged 18 to 60 and to take place at six locations in the Caribbean . In 2021, two vaccine manufacturers, one in France, the other in the United States, reported successful completion of phase II clinical trials.

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Chikungunya

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Epidemiology of chikungunya

Chikungunya is a mosquito-borne alpha virus that was first isolated after a 1952 outbreak in modern-day Tanzania. The virus has circulated in forested regions of sub-Saharan African in cycles involving nonhuman primate hosts and arboreal mosquito vectors. Phylogenetic studies indicate that the urban transmission cycle—the transmission of a pathogen between humans and mosquitoes that exist in urban environments—was established on multiple occasions from strains occurring on the eastern half of Africa in non-human primate hosts. This emergence and spread beyond Africa may have started as early as the 18th century. Currently, available data does not indicate whether the introduction of chikungunya into Asia occurred in the 19th century or more recently, but this epidemic Asian strain causes outbreaks in India and continues to circulate in Southeast Asia. A number of chikungunya outbreaks have occurred since 2005. However, As of the latest data available, developed countries have yet to report a confirmed indigenous case of chikungunya. An analysis of the chikungunya virus 's genetic code suggests that the increased severity of the 2005–present outbreak may be due to a change in the genetic sequence, altering the virus' viral coat protein, which potentially allows it to multiply more easily in mosquito cells. The change allows the virus to use the Asian tiger mosquito (an invasive species ) as a vector in addition to the more strictly tropical main vector, Aedes aegypti . In July 2006, a team analyzed the virus' RNA and determined the genetic changes that have occurred in various strains of the virus and identified those genetic sequences which led to the increased virulence of recent strains. The virus, CHIKV, is a small, enveloped virus making it part of the alphavirus family Togaviridae . This characteristic improves the viruses ability to enter into the body and impact those most affected such as individuals over 65 years of age and individuals with underlying medical conditions. Individuals below the age of 30 are found to have a faster recovery time with the reasoning unknown at this time. Outbreaks of chikungunya, on average, have low mortality rates. As it is generally a nonfatal disease, prevalence rates during most outbreaks are higher than incidence rates. Recently, it was discovered that approximately 39% of the worldwide population resides in environments where the chikungunya virus is endemic. The spikes of transmission have increased the worldwide fatal cases to 350 people per year as of October 2023 to 87 deaths in 2022. Few studies have thoroughly investigated the risks to those living in medically insufficient areas, but some surveys suggest higher rates of chronic effects. Challenges relating to staffing and financing in less-developed countries may contribute to the underreporting of cases. Current data on the co-morbidities of chikungunya infection states that individuals with severe cases of chikungunya have an increased prevalence of cardiac conditions along with diabetes and respiratory difficulties. With the exception of asthma, the risk of each concurrent condition with CHIKV infections increases with age. While the long term effects still need to be investigated, on average, 40% individuals with the multiple chikungunya virus infections experience persistent disabilities after 6 months and 28% of the people still had it after 18 months. Modern studies suggest a correlation between elevated CHIKV infections and risk factors including individuals that previously experienced joint-related pains and conditions, those aged 45 and above, and individuals of the female gender. The largest outbreak of chikungunya ever recorded at the time occurred on the island of Réunion in the western rim of the Indian Ocean from late March 2005 to February 2006. At its height, the incidence peaked at about 25,000 cases per week or 3500 daily in early 2006. After an initial peak in May 2005, the incidence decreased and remained stable through the summer hemisphere winter, rising again at the beginning of October 2005. By mid-December, when southern hemisphere summer temperatures are favorable for the mosquito vector, the incidence began to rise dramatically into the first two months of 2006. The number of reported cases was thought to be underestimated. The case-fatality ratio for chikungunya fever during the outbreak was 1 in 1000. The French government sent several hundred troops to help eradicate mosquitoes. Although confirmed cases were much lower, some estimates based on extrapolations from the number detected by sentinel physicians suggested that as many as 110,000 of Réunion's population of 800,000 people may have been infected. Twelve cases of meningoencephalitis cases were confirmed to be associated with chikungunya infection. Other countries in the southwest Indian Ocean reported cases as well, including Mauritius and the Seychelles , and in Madagascar , the Comoros , and Mayotte .In 2006, there was a large outbreak in India. States affected by the outbreak were Andhra Pradesh , Andaman & Nicobar Islands , Tamil Nadu , Karnataka , Maharashtra , Gujarat , Madhya Pradesh , Kerala and Delhi . The initial cases were reported from Hyderabad and Secunderabad as well as from Anantpur district as early as November and December 2005 and is continue unabated. In Hyderabad alone an average practitioner saw anywhere between 10 and 20 cases every day. Some deaths have been reported but it was thought to be due mainly to the inappropriate use of antibiotics and anti-inflammatory tablets. The major cause of mortality is due to severe dehydration, electrolyte imbalance and loss of glycemic control. Recovery is the rule except for about 3 to 5% incidence of prolonged arthritis. As this virus can cause thrombocytopenia , injudicious use of these drugs can cause erosions in the gastric epithelium leading to exsanguinating upper GI bleed (due to thrombocytopenia). Also the use of steroids for the control of joint pains and inflammation is dangerous and completely unwarranted. On average there are around 5,300 cases being treated every day. This figure is only from public sector. The figures from the private sector combined would be much higher. [ citation needed ] There have been reports of large scale outbreak of this virus in Southern India. At least 80,000 people in Gulbarga, Tumkur, Bidar, Raichur, Bellary, Chitradurga, Davanagere, Kolar and Bijapur districts in Karnataka state are known to have been affected since December 2005. A separate outbreak of chikungunya fever was reported from Malegaon town in Nasik district, Maharashtra state, in the first two weeks of March 2006, resulting in over 2000 cases. In Orissa state, at most 5000 cases of fever with muscle aches and headache were reported between February 27 and March 5, 2006. In Bangalore , the state capital of Karnataka (India), there seemed to be an outbreak of chikungunya in May 2006 with arthralgia/arthritis and rashes. As well as in the neighbouring state of Andhra Pradesh. In the 3rd week of May 2006 the outbreak of chikungunya in North Karnataka was severe. All the North Karnataka districts specially Gulbarga, Koppal, Bellary, Gadag, Dharwad were affected. The people of this region are hence requested to be alert. Stagnation of water which provides fertile breeding grounds for the vector ( Aedes aegypti ) should be avoided. The latest outbreak is in Tamil Nadu , India - 20,000 cases have been reported in June 2006. Earlier it was found spreading mostly in the outskirts of Bangalore, but now it has started spreading in the city also (Updated 30/06/2006). More than 300,000 people are affected in Karnataka as of July 2006. Reported on 29/06/2006, Chennai—fresh cases of this disease has been reported in local hospitals. A heavy effect has been reflected in south TN districts like Kanyakumari and Tirunelveli. Residents of Chennai are warned against the painful disease. [ citation needed ] June 2006— Andaman Islands (India) chikungunya cases had been registered virtually for the first time in the month of June 2006. In the beginning of the September cases have gone as much as in thousands. As reported in a local news magazine it has taken the state of epidemic in Andamans. Health authorities are doing their best to handle the situation. Relapsed cases have been noticed with severe pain and swelling in the lower limbs, vomiting and general weakness. [ citation needed ] As of July 2006, nearly 50,000 people were affected in Salem, Tamil Nadu . As of August 2006, nearly 100,000 people were infected in Tamil Nadu. Chennai , capital of Tamil Nadu is one of the worst affected. On 24 August 2006, The Hindu newspaper reported that the Indian states of Tamil Nadu, Karnataka, Andhra Pradesh, Maharashtra, Madhya Pradesh, Gujarat and Kerala had reported 1.1 million (11 lakh) cases. The government's claim of no deaths is questioned. In September 2007, 130 cases were confirmed in the province of Ravenna, Northern Italy, in the contiguous towns of Castiglione di Cervia and Castiglione di Ravenna . One person died. The source of the outbreak was an Indian from Kerala, India. By the end of September 2009, the Thai Ministry of Health reported more than 42,000 cases during the previous year in 50 provinces in the south of Thailand, including the popular tourist destination of Phuket . About 14 years had lapsed since the last appearance of the disease. In May 2009 the provincial hospital in Trang Province prematurely delivered a 2.7 kg (6 pounds) male baby from his chikungunya-infected mother in the hopes of preventing mother-foetus virus transmission. After a cesarean delivery , the physicians discovered that he had also been infected with the chikungunya virus, and put him under intensive care . The child died at six days from respiratory complications, possibly the only death from the outbreak, but the cause of death may not have been chikungunya since the child was delivered prematurely . The Thai physicians gave a preliminary presumption that chikungunya virus might be transmitted from a mother to her foetus . Outbreaks in the Pacific Islands began in New Caledonia in 2011 and have since occurred in a number of Pacific countries. Fully 1/2 of the entire population of French Polynesia has come down with chikungunya Asian genotype (130,000 cases with 14 dead), exploding from a month earlier with 35,000 cases in December 2014; the first ever case was in 2013.An outbreak occurred in Cambodia with at least 1500 confirmed cases. Provinces for which affection was confirmed were: Preah Vihear, Battambang, Kampong Thom, Kampong Chhnang, Kandal, Kampong Speu and Takeo. In December 2013, it was confirmed that chikungunya was being locally transmitted in the Americas for the first time in the French Caribbean dependency of St. Martin, with 66 confirmed cases and suspected cases of around 181. It is the first time in the Americas that the disease has spread to humans from a population of infected mosquitoes. By mid-January 2014, a number of cases had been confirmed in five countries: St. Martin, Saint Barthélemy , Martinique , Guadeloupe , and the British Virgin Islands . At the start of April, at least ten nations had reported cases. By the start of May, there were more than 4,100 probable cases, and 31,000 suspected cases spanning 14 countries, including French Guiana , the only non-island nation with at least one reported case. On May 1, the Caribbean Public Health Agency (CARPHA) declared a Caribbean-wide epidemic of the virus. As of 21 January 2014, no cases had been reported in Puerto Rico . But by 15 July 2014, over 400 cases had been reported and health authorities believed the number of actual cases (i.e., including unreported cases) was much higher. By November 2014 the Pan American Health Organization reported about 800,000 suspected chikungunya cases in the Caribbean alone. On July 17, 2014, the first chikungunya case acquired in the United States was reported in Florida by the Centers for Disease Control and Prevention in a man who had not recently traveled outside the United States. Shortly after another case was reported of a person in Florida being infected by the virus, not having traveled outside the U.S. These were the first two cases where the virus was passed directly by mosquitoes to persons on the U.S. mainland. Aside from the locally acquired infections, there were 484 other cases reported in the United States as of 5 August 2014. As of 11 September 2014, the number of reported cases in Puerto Rico for the year was 1,636. By 28 October, that number had increased to 2,974 confirmed cases with over 10,000 cases suspected. In September 2014, the Central University of Venezuela stated that there could be between 65,000 and 117,000 Venezuelans infected with chikungunya. Health Minister Nancy Pérez stated that only 400 Venezuelans were infected with chikungunya On October 20, 2014, 11 locally acquired cases of chikungunya were reported in Montpellier , Languedoc-Roussillon , in the South of France. 449 imported cases of chikungunya were also reported throughout France during the period May–November 2014. As of December 2014, Costa Rica had 47 reported cases of chikungunya, 40 of which originated abroad, while 7 were locally acquired. In June 2014 six cases of the virus were confirmed in Brazil, two in the city of Campinas in the state of São Paulo. The six cases are Brazilian army soldiers who had recently returned from Haiti, where they were participating in the reconstruction efforts as members of the United Nations Stabilisation Mission in Haiti . The information was officially released by Campinas municipality, which considers that it has taken the appropriate actions. On 25 September 2014, official authorities in El Salvador report over 30,000 confirmed cases of this new epidemic. On 7 November 2014 Mexico reported an outbreak of chikungunya, acquired by local transmission, in southern state of Chiapas . The outbreak extends across the coastline from the Guatemala border to the neighbouring state of Oaxaca . Health authorities have reported a cumulative load of 39 laboratory-confirmed cases (by the end of week 48). No suspect cases have been reported. The first cases were officially confirmed in July 2014. Between that month and the end of 2014, as reported by the Colombian Health Institute ( Instituto Nacional de Salud - INS (in Spanish) ), there were 82,977 clinically confirmed cases and 611 cases confirmed through laboratory tests, bringing the total of confirmed cases during 2014 in Colombia to 83,588, 7 of which led to deaths. These cases were reported in the following regions: Amazonas, Atlántico, Arauca, Antioquia, Barranquilla, Bolívar, Boyacá, Caldas, Cartagena, Casanare, Cauca, Cesar, Córdoba, Cundinamarca, Huila, La Guajira, Magdalena, Meta, Putumayo, Nariño, Norte de Santander, Sucre, Santander, Santa Marta, Risaralda, Tolima, San Andrés and Valle del Cauca. According to news outlets, as of January 2015 at least one major city ( Medellín ) has issued sanitary alerts due to the expanding epidemic. By January 2015 the epidemic is considered to be in the initial expansion phase and it is expected by the Colombian National Health Institute (Instituto Nacional de Salud - INS) that the total number of cases will reach around 700,000 by the end of 2015 due to the in-country massive travel of tourists to and from regions where cases of the disease have been confirmed and the vector A. aegypti is indigenous . It is expected that the disease will become endemic and sustain itself, with a pattern of outbreaks similar to dengue fever , due to the fact that both vector and natural reservoirs are indigenous in large areas of the country. On 24 September 2015, the Ministry of Health and Social Protection of Colombia officially declared the country free of chikungunya. There were 441,000 reported cases but the government estimated the infected to reach the 873,000. The earliest case was reported on 7 January 2019 in Diosso , Republic of the Congo , and an outbreak was declared by the government on 9 February. By 14 April, 6,149 suspected cases had been reported, with Kouilou Department worst affected (47% of cases); suspected cases have also been reported in the Bouenza , Brazzaville , Lékoumou , Niari , Plateaux , Pointe-Noire and Pool departments. There have been no deaths reported.

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Mosquito-borne disease

Mosquito-borne diseases or mosquito-borne illnesses are diseases caused by bacteria, viruses or parasites transmitted by mosquitoes . Nearly 700 million people get a mosquito-borne illness each year, resulting in over 725,000 deaths. Diseases transmitted by mosquitoes include malaria , dengue , West Nile virus , chikungunya , yellow fever , filariasis , tularemia , dirofilariasis , Japanese encephalitis , Saint Louis encephalitis , Western equine encephalitis , Eastern equine encephalitis , Venezuelan equine encephalitis , Ross River fever , Barmah Forest fever , La Crosse encephalitis , and Zika fever , as well as newly detected Keystone virus and Rift Valley fever . In January 2024, an Australian research group proved that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer is transmitted by mosquitos. This is the first described mosquito-borne transmission of a bacterial disease. There is no evidence as of April 2020 that COVID-19 can be transmitted by mosquitoes, and it is extremely unlikely this could occur. The female mosquito of the genus Anopheles may carry the malaria parasite . Four different species of protozoa cause malaria: Plasmodium falciparum , Plasmodium malariae , Plasmodium ovale and Plasmodium vivax (see Plasmodium ). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by the World Health Organization (WHO). The death toll increased to one million as of 2018 according to the American Mosquito Control Association. In January 2024, a publication by an Australian research group demonstrated significant genetic similarity between Mycobacterium ulcerans in humans and possums, compared to PCR screening of M. ulcerans from trapped Aedes notoscriptus mosquitoes, and concluded that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer , is transmitted by mosquitos. Botflies are known to parasitize humans or other mammalians, causing myiasis , and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly Dermatobia hominis attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of the larvae. [ citation needed ] Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis ) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability. [ citation needed ] The viral diseases yellow fever , dengue fever , Zika fever and chikungunya are transmitted mostly by Aedes aegypti mosquitoes. [ citation needed ] Other viral diseases like epidemic polyarthritis , Rift Valley fever , Ross River fever , St. Louis encephalitis , West Nile fever , Japanese encephalitis , La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occur in the United States where they cause disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma, and death. Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses . West Nile virus was accidentally introduced into the US in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006. Other species of Aedes as well as Culex and Culiseta are also involved in the transmission of disease. [ citation needed ] Myxomatosis is spread by biting insects, including mosquitoes. The female mosquito of the genus Anopheles may carry the malaria parasite . Four different species of protozoa cause malaria: Plasmodium falciparum , Plasmodium malariae , Plasmodium ovale and Plasmodium vivax (see Plasmodium ). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by the World Health Organization (WHO). The death toll increased to one million as of 2018 according to the American Mosquito Control Association. In January 2024, a publication by an Australian research group demonstrated significant genetic similarity between Mycobacterium ulcerans in humans and possums, compared to PCR screening of M. ulcerans from trapped Aedes notoscriptus mosquitoes, and concluded that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer , is transmitted by mosquitos. Botflies are known to parasitize humans or other mammalians, causing myiasis , and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly Dermatobia hominis attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of the larvae. [ citation needed ]Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis ) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability. [ citation needed ]The viral diseases yellow fever , dengue fever , Zika fever and chikungunya are transmitted mostly by Aedes aegypti mosquitoes. [ citation needed ] Other viral diseases like epidemic polyarthritis , Rift Valley fever , Ross River fever , St. Louis encephalitis , West Nile fever , Japanese encephalitis , La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occur in the United States where they cause disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma, and death. Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses . West Nile virus was accidentally introduced into the US in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006. Other species of Aedes as well as Culex and Culiseta are also involved in the transmission of disease. [ citation needed ] Myxomatosis is spread by biting insects, including mosquitoes. A mosquito's period of feeding is often undetected; the bite only becomes apparent because of the immune reaction it provokes. When a mosquito bites a human, it injects saliva and anti-coagulants . With the initial bite to an individual, there is no reaction, but with subsequent bites, the body's immune system develops antibodies . The bites become inflamed and itchy within 24 hours. This is the usual reaction in young children. With more bites, the sensitivity of the human immune system increases, and an itchy red hive appears in minutes where the immune response has broken capillary blood vessels and fluid has collected under the skin. This type of reaction is common in older children and adults. Some adults can become desensitized to mosquitoes and have little or no reaction to their bites, while others can become hyper-sensitive with bites causing blistering, bruising, and large inflammatory reactions, a response known as skeeter syndrome . One study found Dengue virus and Zika virus altered the skin bacteria of rats in a way that caused their body odor to be more attractive to mosquitoes. Symptoms of illness are specific to the type of viral infection and vary in severity, based on the individuals infected. Symptoms vary in severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare. Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those with cancer, diabetes, hypertension, and kidney disease. Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal. People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications. Symptoms vary in severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare. Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those with cancer, diabetes, hypertension, and kidney disease. Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal. People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications. Mosquitoes carrying such arboviruses stay healthy because their immune systems recognizes the virions as foreign particles and "chop off" the virus' genetic coding, rendering it inert. Human infection with a mosquito-borne virus occurs when a female mosquito bites someone while its immune system is still in the process of destroying the virus's harmful coding. [ clarification needed ] It is not completely known how mosquitoes handle eukaryotic parasites to carry them without being harmed. Data has shown that the malaria parasite Plasmodium falciparum alters the mosquito vector's feeding behavior by increasing frequency of biting in infected mosquitoes, thus increasing the chance of transmitting the parasite. The mechanism of transmission of this disease starts with the injection of the parasite into the victim's blood when malaria-infected female Anopheles mosquitoes bite into a human being. The parasite uses human liver cells as hosts for maturation where it will continue to replicate and grow, moving into other areas of the body via the bloodstream. The spread of this infection cycle then continues when other mosquitoes bite the same individual. The result will cause that mosquito to ingest the parasite and allow it to transmit the Malaria disease into another person through the same mode of bite injection. Flaviviridae viruses transmissible via vectors like mosquitoes include West Nile virus and yellow fever virus, which are single stranded, positive-sense RNA viruses enveloped in a protein coat. Once inside the host's body, the virus will attach itself to a cell's surface through receptor-mediated endocytosis. This essentially means that the proteins and DNA material of the virus are ingested into the host cell. The viral RNA material will undergo several changes and processes inside the host's cell so that it can release more viral RNA that can then be replicated and assembled to infect neighboring host cells. Mosquito-borne flaviviruses also encode viral antagonists to the innate immune system in order to cause persistent infection in mosquitoes and a broad spectrum of diseases in humans. The data on transmissibility via insect vectors of hepatitis C virus, also belonging to family Flaviviridae (as well as for hepatitis B virus, belonging to family Hepadnaviridae ) are inconclusive. WHO states that "There is no insect vector or animal reservoir for HCV", while there are experimental data supporting at least the presence of [PCR]-detectable hepatitis C viral RNA in Culex mosquitoes for up to 13 days. Currently, there are no specific vaccine therapies for West Nile virus approved for humans; however, vaccines are available and some show promise for animals, as a means to intervene with the mechanism of spreading such pathogens. Doctors can typically identify a mosquito bite by sight. A doctor will perform a physical examination and ask about medical history as well as any travel history. Be ready to give details on any international trips, including the dates you were traveling, the countries you visited and any contact you had with mosquitoes. Diagnosing dengue fever can be difficult, as its symptoms often overlap with many other diseases such as malaria and typhoid fever . Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment. Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation. A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test. Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months. Diagnosing dengue fever can be difficult, as its symptoms often overlap with many other diseases such as malaria and typhoid fever . Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment. Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation. A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test. Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months. There is a re-emergence of mosquito vectored viruses (arthropod-borne viruses) called arboviruses carried by the Aedes aegypti mosquito. Examples are the Zika virus, chikungunya virus, yellow fever and dengue fever. The re-emergence of the viruses has been at a faster rate, and over a wider geographic area, than in the past. The rapid re-emergence is due to expanding global transportation networks, the mosquito's increasing ability to adapt to urban settings, the disruption of traditional land use and the inability to control expanding mosquito populations. Like malaria, arboviruses do not have a vaccine. (The only exception is yellow fever.) Prevention is focused on reducing the adult mosquito populations, controlling mosquito larvae and protecting individuals from mosquito bites. Depending on the mosquito vector, and the affected community, a variety of prevention methods may be deployed at one time. The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors Anopheles gambiae and Anopheles funestus which carry malaria. Because the Anopheles gambiae feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported Anopheles vector resistance to pyrethroid insecticides. Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the Aedes aegypti mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes. There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with icaridin or DEET is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes. There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine , and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV . The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015. To date, there are relatively few vaccines against mosquito-borne diseases, this is due to the fact that most viruses and bacteria caused by mosquitos are highly mutatable. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases. The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the Aedes aegypti mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention. The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors Anopheles gambiae and Anopheles funestus which carry malaria. Because the Anopheles gambiae feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported Anopheles vector resistance to pyrethroid insecticides. Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the Aedes aegypti mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes. There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with icaridin or DEET is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes. There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine , and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV . The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015. To date, there are relatively few vaccines against mosquito-borne diseases, this is due to the fact that most viruses and bacteria caused by mosquitos are highly mutatable. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases. The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the Aedes aegypti mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention. Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation . Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net . Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs. Dengue fever occurs via Aedes aegypti mosquito (it acts as a vector). Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics . Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used. There are no treatment modalities for acute and chronic chikungunya that currently exist. Most treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis . In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains. The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies , the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world. Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation . Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net . Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs. Dengue fever occurs via Aedes aegypti mosquito (it acts as a vector).Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics . Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used. There are no treatment modalities for acute and chronic chikungunya that currently exist. Most treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis . In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains. The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies , the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world. Mosquito-borne diseases, such as dengue fever and malaria , typically affect developing countries and areas with tropical climates. Mosquito vectors are sensitive to climate changes and tend to follow seasonal patterns. Between years there are often dramatic shifts in incidence rates. The occurrence of this phenomenon in endemic areas makes mosquito-borne viruses difficult to treat. Dengue fever is caused by infection through viruses of the family Flaviviridae. The illness is most commonly transmitted by Aedes aegypti mosquitoes in tropical and subtropical regions. Dengue virus has four different serotypes, each of which are antigenically related but have limited cross-immunity to reinfection. Although dengue fever has a global incidence of 50–100 million cases, only several hundreds of thousands of these cases are life-threatening. The geographic prevalence of the disease can be examined by the spread of Aedes aegypti . Over the last twenty years, there has been a geographic spread of the disease. Dengue incidence rates have risen sharply within urban areas which have recently become endemic hot spots for the disease. The recent spread of Dengue can also be attributed to rapid population growth, increased coagulation in urban areas, and global travel. Without sufficient vector control, the dengue virus has evolved rapidly over time, posing challenges to both government and public health officials. [ citation needed ] Malaria is caused by a protozoan called Plasmodium falciparum . P. falciparum parasites are transmitted mainly by the Anopheles gambiae complex in rural Africa. In just this area, P. falciparum infections comprise an estimated 200 million clinical cases and 1 million annual deaths. 75% of individuals affected in this region are children. As with dengue, changing environmental conditions have led to novel disease characteristics. Due to increased illness severity, treatment complications, and mortality rates, many public health officials concede that malaria patterns are rapidly transforming in Africa. Scarcity of health services, rising instances of drug resistance, and changing vector migration patterns are factors that public health officials believe contribute to malaria's dissemination. Climate heavily affects mosquito vectors of malaria and dengue. Climate patterns influence the lifespan of mosquitos as well as the rate and frequency of reproduction. Climate change impacts have been of great interest to those studying these diseases and their vectors. Additionally, climate impacts mosquito blood feeding patterns as well as extrinsic incubation periods. Climate consistency gives researchers an ability to accurately predict annual cycling of the disease but recent climate unpredictability has eroded researchers' ability to track the disease with such precision.In many insect species, such as Drosophila melanogaster , researchers found that a natural infection with the bacteria strain Wolbachia pipientis increases the fitness of the host by increasing resistance to RNA viral infections. Robert L. Glaser and Mark A. Meola investigated Wolbachia -induced resistance to West Nile virus (WNV) in Drosophila melanogaster (fruit flies). Two groups of fruit flies were naturally infected with Wolbachia . Glaser and Meola then cured one group of fruit flies of Wolbachia using tetracycline. Both the infected group and the cured groups were then infected with WNV. Flies infected with Wolbachia were found to have a changed phenotype that caused resistance to WNV. The phenotype was found to be caused by a "dominant, maternally transmitted, cytoplasmic factor". The WNV-resistance phenotype was then reversed by curing the fruit flies of Wolbachia . Since Wolbachia is also maternally transmitted, it was found that the WNV-resistant phenotype is directly related to the Wolbachia infection. West Nile virus is transmitted to humans and animals through the Southern house mosquito, Culex quinquefasciatus . Glaser and Meola knew vector compatibility could be reduced through Wolbachia infection due to studies done with other species of mosquitoes, mainly, Aedes aegypti . Their goal was to transfer WNV resistance to Cx. quinquefasciatus by inoculating the embryos of the mosquito with the same strain of Wolbachia that naturally occurred in the fruit flies. Upon infection, Cx. quinquefasciatus showed an increased resistance to WNV that was transferable to offspring. The ability to genetically modify mosquitoes in the lab and then have the infected mosquitoes transmit it to their offspring showed that it was possible to transmit the bacteria to wild populations to decrease human infections. [ citation needed ] In 2011, Ary Hoffmann and associates produced the first case of Wolbachia -induced arbovirus resistance in wild populations of Aedes aegypti through a small project called Eliminate Dengue: Our Challenge. This was made possible by an engineered strain of Wolbachia termed w Mel that came from D. melanogaster . The transfer of w Mel from D. melanogaster into field-caged populations of the mosquito Aedes aegypti induced resistance to dengue, yellow fever, and chikungunya viruses. Although other strains of Wolbachia also reduced susceptibility to dengue infection, they also put a greater demand on the fitness of Ae. aegypti . w Mel was different in that it was thought to only cost the organism a small portion of its fitness. w Mel-infected Ae. aegypti were released into two residential areas in the city of Cairns, Australia over a 14-week period. Hoffmann and associates, released a total of 141,600 infected adult mosquitoes in Yorkeys Knob suburb and 157,300 in Gordonvale suburb. After release, the populations were monitored for three years to record the spread of w Mel. Population monitoring was gauged by measuring larvae laid in traps. At the beginning of the monitoring period but still within the release period, it was found that w Mel-infected Ae. aegypti had doubled in Yorkeys Knob and increased 1.5-fold in Gordonvale. Uninfected Ae. aegypti populations were in decline. By the end of the three years, w Mel-infected Ae. aegypti had stable populations of about 90%. However, these populations were isolated to the Yorkeys Knob and Gordonvale suburbs due to unsuitable habitat surrounding the neighborhoods. Although populations flourished in these areas with nearly 100% transmission, no signs of spread were noted, proving disappointing for some. Following this experiment, Tom L. Schmidt and his colleagues conducted an experiment releasing Wolbachia -infected Aedes aegypti using different site selection methods occurred in different areas of Cairns during 2013. The release sites were monitored over two years. This time the release was done in urban areas that were adjacent to adequate habitat to encourage mosquito dispersal. Over the two years, the population doubled, and spatial spread was also increased, unlike the first release, giving ample satisfactory results. By increasing the spread of the Wolbachia -infected mosquitoes, the researchers were able to establish that population of a large city was possible if the mosquitoes were given adequate habitat to spread into upon release in different local locations throughout the city. In both of these studies, no adverse effects on public health or the natural ecosystem occurred. This made it an extremely attractive alternative to traditional insecticide methods given the increased pesticide resistance occurring from heavy use. From the success seen in Australia, the researchers were able to begin operating in more threatened portions of the world. The Eliminate Dengue program spread to 10 countries throughout Asia, Latin America, and the Western Pacific blooming into the non-profit organization, World Mosquito Program, as of September 2017. They still use the same technique of infecting wild populations of Ae. aegypti as they did in Australia, but their target diseases now include Zika, chikungunya and yellow fever as well as dengue. Although not alone in their efforts to use Wolbachia- infected mosquitoes to reduce mosquito-borne disease, the World Mosquito Program method is praised for being self-sustaining in that it causes permanent phenotype change rather than reducing mosquito populations through cytoplasmic incompatibility through male-only dispersal.

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Chikungunya

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Malir District

Malir District ( Urdu : ضلع ٠لير ) is an administrative district of Karachi Division in Sindh , Pakistan .Before the independence of Pakistan , there were small villages of Sindhi and Kalmati Baloch in the Gadap Town and Malir Town of modern Karachi. Now both towns are developed as the suburbs of the city because of the urban sprawl . Malir has been regarded in history as the countryside of Karachi City due to its open atmosphere and lush green farms, but now these are no more. Malir was once famous for its fruit and vegetable farms; but, now due to severe scarcity of groundwater, these farmlands are being converted into residential areas, thus increasing urbanization and environmental degradation . The Society for Conservation and Protection of Environment (SCOPE) has been concerned about drought and desertification in Malir district and has launched a campaign against illegal sand and gravel mining in dry river beds of Malir and its tributaries. Because sand and gravel mining cause lowering of ground water, as rainwater can cannot percolate in the aquifer. SCOPE is developing rainwater reservoirs in drought affected rural areas. Malir has been regarded in history as the countryside of Karachi City due to its open atmosphere and lush green farms, but now these are no more. Malir was once famous for its fruit and vegetable farms; but, now due to severe scarcity of groundwater, these farmlands are being converted into residential areas, thus increasing urbanization and environmental degradation . The Society for Conservation and Protection of Environment (SCOPE) has been concerned about drought and desertification in Malir district and has launched a campaign against illegal sand and gravel mining in dry river beds of Malir and its tributaries. Because sand and gravel mining cause lowering of ground water, as rainwater can cannot percolate in the aquifer. SCOPE is developing rainwater reservoirs in drought affected rural areas. Malir District was established in 1996. Malir District was abolished in 2000 and divided into three towns namely: On 11 July 2011, Sindh Government restored again Malir District. In 2022, Malir District was divided into three "Town Municipal Corporation " namely: Headed by its elected Chairman and a vice-chairman. and also 6 subdivisions namely: Each subdivision's headed by an Assistant Commissioner . At the time of the 2017 census, Malir district had 317,318 households and a population of 1,924,346. Malir had a sex ratio of 870 females per 1000 males and a literacy rate of 63.69%: 69.85% for males and 56.43% for females. 1,066,712 (55.43%) lived in urban areas. 504,348 (26.21%) were under 10 years of age. In 2023, the district had 416,512 households and a population of 2,403,959. The majority religion is Islam, with 96.39% of the population. Christianity is practiced by 1.78% and Hinduism (including Scheduled Castes) is practiced by 1.77% of the population. Languages of Malir district (2017) At the time of the 2017 census, 31.37% of the population spoke Sindhi , 19.37% Pashto , 12.91% Urdu , 12.08% Punjabi , 8.18% Balochi , 6.83% Hindko , 3.96% Saraiki and 1.26% Brahui as their first language. Languages of Malir district (2017) At the time of the 2017 census, 31.37% of the population spoke Sindhi , 19.37% Pashto , 12.91% Urdu , 12.08% Punjabi , 8.18% Balochi , 6.83% Hindko , 3.96% Saraiki and 1.26% Brahui as their first language. Due to pollution, mainly resulting from garbage dumps and overflow of sewerage water, Emergency declared in Malir Town, as thousands of patients were affected by mysterious Chikungunya virus in December, 2016. Despite joint denial by WHO and Health Ministry of Pakistan, Provincial Government of Sindh discloses that aedes aegypti mosquito is responsible for spreading Chikungunya in the area.

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Chikungunya

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Aedes albopictus

Culex albopictus Skuse , 1894 Aedes albopictus ( Stegomyia albopicta ), from the mosquito (Culicidae) family , also known as the (Asian) tiger mosquito or forest mosquito , is a mosquito native to the tropical and subtropical areas of Southeast Asia. In the past few centuries, however, this species has spread to many countries through the transport of goods and international travel. It is characterized by the white bands on its legs and body. This mosquito has become a significant pest in many communities because it closely associates with humans (rather than living in wetlands), and typically flies and feeds in the daytime in addition to at dusk and dawn. The insect is called a tiger mosquito for its striped appearance, which resembles that of the tiger . Ae. albopictus is an epidemiologically important vector for the transmission of many viral pathogens , including the yellow fever virus , dengue fever , and Chikungunya fever , as well as several filarial nematodes such as Dirofilaria immitis . Aedes albopictus is capable of hosting the Zika virus and is considered a potential vector for Zika transmission among humans.In 1894, a British-Australian entomologist, Frederick A. Askew Skuse , was the first to scientifically describe the Asian tiger mosquito, which he named Culex albopictus ( lat. culex "gnat", "midge" and albopictus "white-painted"). Later, the species was assigned to the genus Aedes ( gr. άηδής , "unpleasant") and referred to as Aedes albopictus . Like the yellow fever mosquito , it belongs to the subgenus Stegomyia (Gr. στέγος , "covered, roofed", referring to the scales that completely cover the dorsal surface in this subgenus, and Î¼Ï Î¯Î± , "fly") within the genus Aedes . In 2004, scientists explored higher-level relationships and proposed a new classification within the genus Aedes and Stegomyia was elevated to the genus level, making Aedes albopictus now Stegomyia albopicta . This is, however, a controversial matter, and the use of Stegomyia albopicta versus Aedes albopictus is continually debated. The adult Asian tiger mosquito is less than 10 mm (0.39 in) long from end to end with a striking white and black pattern. The variation of the body size in adult mosquitoes depends on the density of the larval population and food supply within the breeding water. Since these circumstances are seldom optimal, the average body size of adult mosquitoes is considerably smaller than 10 mm. For example, the average length of the abdomen was calculated to be 2.63 mm (0.104 in) , the wings 2.7 mm (0.11 in) , and the proboscis 1.88 mm (0.074 in) . The males are roughly 20% smaller than the females, but they are morphologically very similar. However, as in all mosquito species, the antennae of the males in comparison to the females are noticeably bushier and contain auditory receptors to detect the characteristic whine, almost inaudible to humans, of the female. The maxillary palps of the males are also longer than their proboscis, whereas the females' maxillary palps are much shorter. (This is typical for the males of the Culicinae .) In addition, the tarsus of the hind legs of the males is more silvery. Tarsomere IV is roughly 75% silver in the males whereas the females' is only about 60% silver. [ citation needed ] The other characteristics do not differentiate between sexes. A single silvery-white line of tight scales begins between the eyes and continues down the dorsal side of the thorax. This characteristic marking is the easiest and surest way to identify the Asian tiger mosquito. [ citation needed ] The proboscis is dark colored, the upper surface of the end segment of the palps is covered in silvery scales, and the labium does not feature a light line on its underside. The compound eyes are distinctly separated from one another. The scute , the dorsal portion of an insect's thoracic segment, is black alongside the characteristic white midline. On the side of the thorax, the scutellum , and the abdomen are numerous spots covered in white-silvery scales. [ citation needed ] Such white-silvery scales can also be found on the tarsus, particularly on the hind legs that are commonly suspended in the air. The bases of tarsomeres I through IV have a ring of white scales, creating the appearance of white and black rings. On the forelegs and middle legs, only the first three tarsomeres have the ring of white scales, whereas tarsomere V on the hind legs is completely white. The femur of each leg is also black with white scales on the end of the "knee". The femora of the middle legs do not feature a silver line on the base of the upper side, whereas, the femora on the hind legs have short white lines on base of the upper side. The tibiae are black on the base and have no white scales. [ citation needed ] The terga on segments II through VI of the abdomen are dark and have an almost triangular silvery-white marking on the base that is not aligned with the silvery bands of scales on the ventral side of the abdomen. The triangular marking and the silvery band are only aligned on abdominal segment VII. The transparent wings have white spots on the base of the costae. With older mosquito specimens, the scales could be partially worn off, making these characteristics not stand out as much. As with other members of the mosquito family, the female is equipped with an elongated proboscis that she uses to collect blood to feed her eggs. The Asian tiger mosquito has a rapid bite and an agility that allows it to escape most attempts by people to swat it. By contrast, the male member of the species primarily feeds on nectar and does not bite. The female lays her eggs near water, not directly into it as other mosquitoes do, but typically near a stagnant pool. However, any open container containing water will suffice for larvae development, even with less than one US fl oz (30 ml) of water. It can also breed in running water, so stagnant pools of water are not its only breeding sites. It is more likely to lay eggs in water sources near flowers than in water sources without flowers. It has a short flight range (less than 200 m (220 yd) ), so breeding sites are likely to be close to where this mosquito is found. Other mosquito species may be visually confused with the tiger mosquito. Comparison with approved pictures is the best way to determine the species with certainty. Behavioral cues like almost-silent flight and difficulty in catching combined with knowledge of the range of local endemic mosquitoes may also aid this process. Some mosquitoes in North America, such as Ochlerotatus canadensis , have a similar leg pattern. In North and South America, Ae. albopictus can be distinguished from Aedes taeniorhynchus since only Ae. albopictus has back markings. In Europe, the mosquito Culiseta annulata , which is very common, but does not occur in high densities, can be mistaken for an Asian tiger mosquito because of its black-and-white-ringed legs. However, this species is missing the distinctive white line that runs from the middle of its head and down the thorax. It is also considerably larger than Ae. albopictus , is not black and white, but rather beige and grey striped, and has wings with noticeable veins and four dark, indistinct spots. The Tree Hole mosquito or Aedes geniculatus – a native to Europe and North Africa – has also been mistaken for Ae. albopictus. This is because the Tree Hole mosquito has very white scales on a very similar body. In the eastern Mediterranean area, Ae. albopictus species can be mistaken for Aedes cretinus , which also belongs to the subgenus Stegomyia and uses similar breeding waters. Aedes cretinus also has a white stripe on the scute , but it ends shortly before the abdomen, and also has two additional stripes to the left and right of the middle stripe. So far Aedes cretinus is only located in Cyprus, Greece, North Macedonia, Georgia and Turkey. In Asia, the Asian tiger mosquito can be mistaken for other members of the subgenus Stegomyia , particularly the yellow fever mosquito Aedes aegypti (the most prevalent species in the tropics and subtropics), because both species display a similar black and white pattern. It can be hard to distinguish Ae. albopictus from the closely related Aedes scutellaris (India, Indonesia, Papua New Guinea , and the Philippines ), Aedes pseudoalbopictus ( India , Indonesia, Malaysia , Myanmar , Nepal, Taiwan , Thailand, and Vietnam ) and Aedes seatoi (Thailand). Like other mosquito species, only the females require a blood meal to develop their eggs. Apart from that, they feed on nectar and other sweet plant juices just as the males do. In regards to host location, carbon dioxide and organic substances produced from the host, humidity, and optical recognition play important roles. [ citation needed ] The search for a host takes place in two phases. First, the mosquito exhibits a nonspecific searching behavior until it perceives host stimulants, whereupon it secondly takes a targeted approach. For catching tiger mosquitoes with special traps, carbon dioxide and a combination of chemicals that naturally occur in human skin ( fatty acids , ammonia , and lactic acid ) are the most attractive. The Asian tiger mosquito particularly bites in forests during the day, so has been known as the forest day mosquito. Depending upon region and biotype, activity peaks differ, but for the most part, they rest during the morning and night hours. They search for their hosts inside and outside human dwellings, but are particularly active outside. The size of the blood meal depends upon the size of the mosquito, but it is usually around 2 μl. Their bites are not necessarily painful, but they are more noticeable than those from other kinds of mosquitoes. Tiger mosquitoes generally tend to bite a human host more than once if they are able to. Ae. albopictus also bites other mammals besides humans, as well as birds. The females are always on the search for a host and are persistent but cautious when it comes to their blood meal and host location. Their blood meal is often broken off before enough blood has been ingested for the development of their eggs, so Asian tiger mosquitoes bite multiple hosts during their development cycle of the egg, making them particularly efficient at transmitting diseases. The mannerism of biting diverse host species enables the Asian tiger mosquito to be a potential bridge vector for certain pathogens that can jump species boundaries, for example the West Nile virus . [ citation needed ] Primarily, other mosquito larvae, flatworms , swimming beetles, fungi , ciliates , paramecia , protozoans which act as parasites, predatory copepods , and spiders are natural enemies of the larval stage of Asian tiger mosquitoes. [ citation needed ] Toxorhynchites larvae, a mosquito genus that does not suck blood, feeds upon other mosquito larvae and are often found with tiger mosquito larvae. Flatworms and small swimming beetles are considered natural predators. Fungi from the genus Coelomomyces (order Blastocladiales ) develop inside the visceral cavity of mosquito larvae. The species Coelomomyces stegomyiae was first found on the Asian tiger mosquito. Paramecia , or ciliates, can also affect Ae. albopictus larvae, and the first detected species was Lambornella stegomyiae (Hymenostomatida: Tetrahymenidae). The virulence, mortality rate, and subsequent possibilities of Lambornella being implemented as a biological remedy to control Ae. albopictus , however, has conflicting views. Sporozoans of the genus Ascogregarina ( Lecudinidae ) infect the larval stage of mosquitoes. The species Ascogregarina taiwanensis was found in Asian tiger mosquitoes. When the adult mosquitoes emerge from their pupal case, they leave the infectious intermediary stage of parasites in the water and close off the infection cycle. Infected adults are generally smaller than non-infected adults and have an insignificantly higher mortality rate; therefore, food supply and larval density apparently play a role. In competitive situations, an infection with sporozoans can also reduce the biological fitness of other uninfected mosquitoes. However, the use of the parasites as an effective biological remedy to control mosquito populations is implausible because the host must reach the adult stage for the transmission of the parasites. Though they do not commonly occur in the natural habitats of Asian tiger mosquitoes, predatory copepods from the family Cyclopidae seem to willingly feed on them given the opportunity. Relatives of different genera could therefore present a possibility in the control of tiger mosquitoes. Predators of adult Ae. albopictus in Malaysia include various spider species. Up to 90% of the gathered spiders from rubber plantations and a cemetery fed upon Asian tiger mosquitoes. Whether the spiders would have an effect on the mosquito population is still unclear. Tiger mosquitoes were abundantly present despite the existence of the spiders. In 1894, a British-Australian entomologist, Frederick A. Askew Skuse , was the first to scientifically describe the Asian tiger mosquito, which he named Culex albopictus ( lat. culex "gnat", "midge" and albopictus "white-painted"). Later, the species was assigned to the genus Aedes ( gr. άηδής , "unpleasant") and referred to as Aedes albopictus . Like the yellow fever mosquito , it belongs to the subgenus Stegomyia (Gr. στέγος , "covered, roofed", referring to the scales that completely cover the dorsal surface in this subgenus, and Î¼Ï Î¯Î± , "fly") within the genus Aedes . In 2004, scientists explored higher-level relationships and proposed a new classification within the genus Aedes and Stegomyia was elevated to the genus level, making Aedes albopictus now Stegomyia albopicta . This is, however, a controversial matter, and the use of Stegomyia albopicta versus Aedes albopictus is continually debated. The adult Asian tiger mosquito is less than 10 mm (0.39 in) long from end to end with a striking white and black pattern. The variation of the body size in adult mosquitoes depends on the density of the larval population and food supply within the breeding water. Since these circumstances are seldom optimal, the average body size of adult mosquitoes is considerably smaller than 10 mm. For example, the average length of the abdomen was calculated to be 2.63 mm (0.104 in) , the wings 2.7 mm (0.11 in) , and the proboscis 1.88 mm (0.074 in) . The males are roughly 20% smaller than the females, but they are morphologically very similar. However, as in all mosquito species, the antennae of the males in comparison to the females are noticeably bushier and contain auditory receptors to detect the characteristic whine, almost inaudible to humans, of the female. The maxillary palps of the males are also longer than their proboscis, whereas the females' maxillary palps are much shorter. (This is typical for the males of the Culicinae .) In addition, the tarsus of the hind legs of the males is more silvery. Tarsomere IV is roughly 75% silver in the males whereas the females' is only about 60% silver. [ citation needed ] The other characteristics do not differentiate between sexes. A single silvery-white line of tight scales begins between the eyes and continues down the dorsal side of the thorax. This characteristic marking is the easiest and surest way to identify the Asian tiger mosquito. [ citation needed ] The proboscis is dark colored, the upper surface of the end segment of the palps is covered in silvery scales, and the labium does not feature a light line on its underside. The compound eyes are distinctly separated from one another. The scute , the dorsal portion of an insect's thoracic segment, is black alongside the characteristic white midline. On the side of the thorax, the scutellum , and the abdomen are numerous spots covered in white-silvery scales. [ citation needed ] Such white-silvery scales can also be found on the tarsus, particularly on the hind legs that are commonly suspended in the air. The bases of tarsomeres I through IV have a ring of white scales, creating the appearance of white and black rings. On the forelegs and middle legs, only the first three tarsomeres have the ring of white scales, whereas tarsomere V on the hind legs is completely white. The femur of each leg is also black with white scales on the end of the "knee". The femora of the middle legs do not feature a silver line on the base of the upper side, whereas, the femora on the hind legs have short white lines on base of the upper side. The tibiae are black on the base and have no white scales. [ citation needed ] The terga on segments II through VI of the abdomen are dark and have an almost triangular silvery-white marking on the base that is not aligned with the silvery bands of scales on the ventral side of the abdomen. The triangular marking and the silvery band are only aligned on abdominal segment VII. The transparent wings have white spots on the base of the costae. With older mosquito specimens, the scales could be partially worn off, making these characteristics not stand out as much. As with other members of the mosquito family, the female is equipped with an elongated proboscis that she uses to collect blood to feed her eggs. The Asian tiger mosquito has a rapid bite and an agility that allows it to escape most attempts by people to swat it. By contrast, the male member of the species primarily feeds on nectar and does not bite. The female lays her eggs near water, not directly into it as other mosquitoes do, but typically near a stagnant pool. However, any open container containing water will suffice for larvae development, even with less than one US fl oz (30 ml) of water. It can also breed in running water, so stagnant pools of water are not its only breeding sites. It is more likely to lay eggs in water sources near flowers than in water sources without flowers. It has a short flight range (less than 200 m (220 yd) ), so breeding sites are likely to be close to where this mosquito is found. Other mosquito species may be visually confused with the tiger mosquito. Comparison with approved pictures is the best way to determine the species with certainty. Behavioral cues like almost-silent flight and difficulty in catching combined with knowledge of the range of local endemic mosquitoes may also aid this process.Some mosquitoes in North America, such as Ochlerotatus canadensis , have a similar leg pattern. In North and South America, Ae. albopictus can be distinguished from Aedes taeniorhynchus since only Ae. albopictus has back markings. In Europe, the mosquito Culiseta annulata , which is very common, but does not occur in high densities, can be mistaken for an Asian tiger mosquito because of its black-and-white-ringed legs. However, this species is missing the distinctive white line that runs from the middle of its head and down the thorax. It is also considerably larger than Ae. albopictus , is not black and white, but rather beige and grey striped, and has wings with noticeable veins and four dark, indistinct spots. The Tree Hole mosquito or Aedes geniculatus – a native to Europe and North Africa – has also been mistaken for Ae. albopictus. This is because the Tree Hole mosquito has very white scales on a very similar body. In the eastern Mediterranean area, Ae. albopictus species can be mistaken for Aedes cretinus , which also belongs to the subgenus Stegomyia and uses similar breeding waters. Aedes cretinus also has a white stripe on the scute , but it ends shortly before the abdomen, and also has two additional stripes to the left and right of the middle stripe. So far Aedes cretinus is only located in Cyprus, Greece, North Macedonia, Georgia and Turkey. In Asia, the Asian tiger mosquito can be mistaken for other members of the subgenus Stegomyia , particularly the yellow fever mosquito Aedes aegypti (the most prevalent species in the tropics and subtropics), because both species display a similar black and white pattern. It can be hard to distinguish Ae. albopictus from the closely related Aedes scutellaris (India, Indonesia, Papua New Guinea , and the Philippines ), Aedes pseudoalbopictus ( India , Indonesia, Malaysia , Myanmar , Nepal, Taiwan , Thailand, and Vietnam ) and Aedes seatoi (Thailand). Like other mosquito species, only the females require a blood meal to develop their eggs. Apart from that, they feed on nectar and other sweet plant juices just as the males do. In regards to host location, carbon dioxide and organic substances produced from the host, humidity, and optical recognition play important roles. [ citation needed ] The search for a host takes place in two phases. First, the mosquito exhibits a nonspecific searching behavior until it perceives host stimulants, whereupon it secondly takes a targeted approach. For catching tiger mosquitoes with special traps, carbon dioxide and a combination of chemicals that naturally occur in human skin ( fatty acids , ammonia , and lactic acid ) are the most attractive. The Asian tiger mosquito particularly bites in forests during the day, so has been known as the forest day mosquito. Depending upon region and biotype, activity peaks differ, but for the most part, they rest during the morning and night hours. They search for their hosts inside and outside human dwellings, but are particularly active outside. The size of the blood meal depends upon the size of the mosquito, but it is usually around 2 μl. Their bites are not necessarily painful, but they are more noticeable than those from other kinds of mosquitoes. Tiger mosquitoes generally tend to bite a human host more than once if they are able to. Ae. albopictus also bites other mammals besides humans, as well as birds. The females are always on the search for a host and are persistent but cautious when it comes to their blood meal and host location. Their blood meal is often broken off before enough blood has been ingested for the development of their eggs, so Asian tiger mosquitoes bite multiple hosts during their development cycle of the egg, making them particularly efficient at transmitting diseases. The mannerism of biting diverse host species enables the Asian tiger mosquito to be a potential bridge vector for certain pathogens that can jump species boundaries, for example the West Nile virus . [ citation needed ]Primarily, other mosquito larvae, flatworms , swimming beetles, fungi , ciliates , paramecia , protozoans which act as parasites, predatory copepods , and spiders are natural enemies of the larval stage of Asian tiger mosquitoes. [ citation needed ] Toxorhynchites larvae, a mosquito genus that does not suck blood, feeds upon other mosquito larvae and are often found with tiger mosquito larvae. Flatworms and small swimming beetles are considered natural predators. Fungi from the genus Coelomomyces (order Blastocladiales ) develop inside the visceral cavity of mosquito larvae. The species Coelomomyces stegomyiae was first found on the Asian tiger mosquito. Paramecia , or ciliates, can also affect Ae. albopictus larvae, and the first detected species was Lambornella stegomyiae (Hymenostomatida: Tetrahymenidae). The virulence, mortality rate, and subsequent possibilities of Lambornella being implemented as a biological remedy to control Ae. albopictus , however, has conflicting views. Sporozoans of the genus Ascogregarina ( Lecudinidae ) infect the larval stage of mosquitoes. The species Ascogregarina taiwanensis was found in Asian tiger mosquitoes. When the adult mosquitoes emerge from their pupal case, they leave the infectious intermediary stage of parasites in the water and close off the infection cycle. Infected adults are generally smaller than non-infected adults and have an insignificantly higher mortality rate; therefore, food supply and larval density apparently play a role. In competitive situations, an infection with sporozoans can also reduce the biological fitness of other uninfected mosquitoes. However, the use of the parasites as an effective biological remedy to control mosquito populations is implausible because the host must reach the adult stage for the transmission of the parasites. Though they do not commonly occur in the natural habitats of Asian tiger mosquitoes, predatory copepods from the family Cyclopidae seem to willingly feed on them given the opportunity. Relatives of different genera could therefore present a possibility in the control of tiger mosquitoes. Predators of adult Ae. albopictus in Malaysia include various spider species. Up to 90% of the gathered spiders from rubber plantations and a cemetery fed upon Asian tiger mosquitoes. Whether the spiders would have an effect on the mosquito population is still unclear. Tiger mosquitoes were abundantly present despite the existence of the spiders. The Asian tiger mosquito originally came from Southeast Asia. In 1966, parts of Asia and the island worlds of India and the Pacific Ocean were denoted as the area of circulation for the Asian tiger mosquito. Ae. albopictus as a native to tropical and subtropical regions with warm and humid climate, is active all year long; however, it has been adapting successfully to cooler, temperate regions, where they hibernate over winter. Eggs from strains in the temperate zones are more tolerant to the cold than ones from warmer regions. The species can even tolerate snow and temperatures under freezing. Adult tiger mosquitoes can survive throughout winter in suitable microhabitats. Since the mid-1960s, the tiger mosquito has spread to Europe, the Americas, the Caribbean, Africa, and the Middle East. As of 2008 Ae. albopictus was one of the 100 world's worst invasive species according to the Global Invasive Species Database. As of 2006, Ae. albopictus was not native to Australia and New Zealand. The species was introduced there multiple times, but has yet to establish itself. This is due to the well-organized entomological surveillance programs in the harbors and airports of these countries. Nevertheless, as of 2006 it has become domestic on the islands in the Torres Strait between Queensland, Australia, and New Guinea. In Europe, Asian tiger mosquitos first emerged in Albania in 1979, introduced through a shipment of goods from China. In 1990–1991, they were most likely brought to Italy in used tires from Georgia (USA), and since then have spread throughout the entire mainland of Italy, as well as parts of Sicily and Sardinia . Since 1999, they have established themselves on the mainland of France, primarily southern France. In 2002, they were also discovered in a vacation town on the island of Corsica , but did not completely establish themselves there until 2005. In Belgium , they were detected in 2000 and 2013, in 2001 in Montenegro, 2003 in Canton Ticino in southern Switzerland , and Greece , 2004 in Spain and Croatia , 2005 in the Netherlands and Slovenia , 2006 in Bosnia and Herzegovina and 2022 in Cyprus. In the fall of 2007, the first tiger mosquito eggs were discovered in Rastatt ( Baden-Wuerttemberg , Germany). Shortly before, they were found in the northern Alps of Switzerland in Canton Aargau. Since 2010, it has also been sighted increasingly in Malta during summer. [ citation needed ] In September 2016, Public Health England found eggs, though no mosquitos, in a lorry park at Folkestone service station on the M20 , near Westenhanger , which is 6 miles West of the Eurotunnel. The Swiss Autobahns are especially of concern. Governments and universities in Switzerland cooperate every year to monitor the invasion using traps at Autobahn rest stations, and also at airports and commercial hubs. In Slovakia , two independent observations events have been observed in recent years: first in 2012 near KoÅ¡ice and the second in 2023 in the populated Ružinov borough of Bratislava . The species had failed to settle during the first occurrence but had likely settled in the latter, increasing the risk of concern for public health and safety. In the United States, this species invaded the Southern United States in the 1980s and rapidly spread northward into novel climate compared to its native range. It was initially found in 1983 in Memphis, Tennessee . then at the Port of Houston in a 1985 shipment of used tires, and spread across the South up the East Coast to become prevalent in the Northeast . It was not discovered in Southern California until 2001, then eradicated for over a decade; however, by 2011, it was again being found in Los Angeles County traps, then over the next two years expanded its range to Kern County and San Diego County . As of 2013 [ update ] , North American land favoring the environmental conditions of the Asian tiger mosquito was expected to more than triple in size in the coming 20 years, especially in urban areas. As of 2017 [ update ] Aedes albopictus mosquitoes have been identified in 1,368 counties in 40 U.S states. A 2019 study in Nature Microbiology that modeled expansion of Aedes albopictus due to climate change, urbanization, and human movement found that the species would likely continue to spread throughout the coming decades. In Latin America, the Asian tiger mosquito was first discovered 1986 in Brazil and in 1988 in Argentina and Mexico , as well. Other parts of Latin America where the Asian tiger mosquito was discovered are the Dominican Republic in 1993, Bolivia , Cuba, Honduras , and Guatemala in 1995, El Salvador in 1996, Paraguay in 1999, Panama in 2002, and Uruguay and Nicaragua in 2003. In Africa, the species was first detected in 1990 in South Africa. In Nigeria , it has been domestic since at least 1991. It spread to Cameroon in 1999/2000, to the Bioko Island of Equatorial Guinea in 2001, and to Gabon in 2006. In the Middle East, the species was detected in Lebanon in 2003 and in Syria in 2005; the first record in Israel was published in 2003. Ae. albopictus can outcompete and even eradicate other species with similar breeding habitats from the very start of its dispersal to other regions and biotopes. In Kolkata , for example, it was observed in the 1960s that egg depositing containers were being settled by the Asian tiger mosquito in city districts where the malaria mosquito (genus Anopheles ) and yellow fever mosquito ( Aedes aegypti ) had both been eliminated by the application of DDT . This may be because primarily the inner walls of the houses were treated with DDT to kill the mosquitoes resting there and fight the malaria mosquito. The yellow fever mosquito also lingers particularly in the inside of buildings and would have been also affected. The Asian tiger mosquito rests in the vicinity of human dwellings would therefore have an advantage over the other two species. In other cases where the yellow fever mosquito was repressed by the Asian tiger mosquito, for instance in Florida, this explanation does not fit. Other hypotheses include competition in the larval breeding waters, differences in metabolism and reproductive biology, or a major susceptibility to sporozoans (Apicomplexa). Another species which was suppressed by the migrating Ae. albopictus was Ae. guamensis in Guam . The Asian tiger mosquito is similar, in terms of its close socialization with humans, to the common house mosquito ( Culex pipiens ). Among other differences in their biology, Culex pipiens prefers larger breeding waters and is more tolerant to cold. In this respect, no significant competition or suppression between the two species likely occurs. A possible competition among mosquito species that all lay their eggs in knotholes and other similar places ( Ae. cretinus , Ae. geniculatus , and Anopheles plumbeus ) has yet to be observed. [ citation needed ] In Europe, the Asian tiger mosquito apparently covers an extensive new niche. This means that no native, long-established species conflict with the dispersal of Ae. albopictus . [ citation needed ]The Asian tiger mosquito originally came from Southeast Asia. In 1966, parts of Asia and the island worlds of India and the Pacific Ocean were denoted as the area of circulation for the Asian tiger mosquito. Ae. albopictus as a native to tropical and subtropical regions with warm and humid climate, is active all year long; however, it has been adapting successfully to cooler, temperate regions, where they hibernate over winter. Eggs from strains in the temperate zones are more tolerant to the cold than ones from warmer regions. The species can even tolerate snow and temperatures under freezing. Adult tiger mosquitoes can survive throughout winter in suitable microhabitats. Since the mid-1960s, the tiger mosquito has spread to Europe, the Americas, the Caribbean, Africa, and the Middle East. As of 2008 Ae. albopictus was one of the 100 world's worst invasive species according to the Global Invasive Species Database. As of 2006, Ae. albopictus was not native to Australia and New Zealand. The species was introduced there multiple times, but has yet to establish itself. This is due to the well-organized entomological surveillance programs in the harbors and airports of these countries. Nevertheless, as of 2006 it has become domestic on the islands in the Torres Strait between Queensland, Australia, and New Guinea. In Europe, Asian tiger mosquitos first emerged in Albania in 1979, introduced through a shipment of goods from China. In 1990–1991, they were most likely brought to Italy in used tires from Georgia (USA), and since then have spread throughout the entire mainland of Italy, as well as parts of Sicily and Sardinia . Since 1999, they have established themselves on the mainland of France, primarily southern France. In 2002, they were also discovered in a vacation town on the island of Corsica , but did not completely establish themselves there until 2005. In Belgium , they were detected in 2000 and 2013, in 2001 in Montenegro, 2003 in Canton Ticino in southern Switzerland , and Greece , 2004 in Spain and Croatia , 2005 in the Netherlands and Slovenia , 2006 in Bosnia and Herzegovina and 2022 in Cyprus. In the fall of 2007, the first tiger mosquito eggs were discovered in Rastatt ( Baden-Wuerttemberg , Germany). Shortly before, they were found in the northern Alps of Switzerland in Canton Aargau. Since 2010, it has also been sighted increasingly in Malta during summer. [ citation needed ] In September 2016, Public Health England found eggs, though no mosquitos, in a lorry park at Folkestone service station on the M20 , near Westenhanger , which is 6 miles West of the Eurotunnel. The Swiss Autobahns are especially of concern. Governments and universities in Switzerland cooperate every year to monitor the invasion using traps at Autobahn rest stations, and also at airports and commercial hubs. In Slovakia , two independent observations events have been observed in recent years: first in 2012 near KoÅ¡ice and the second in 2023 in the populated Ružinov borough of Bratislava . The species had failed to settle during the first occurrence but had likely settled in the latter, increasing the risk of concern for public health and safety. In the United States, this species invaded the Southern United States in the 1980s and rapidly spread northward into novel climate compared to its native range. It was initially found in 1983 in Memphis, Tennessee . then at the Port of Houston in a 1985 shipment of used tires, and spread across the South up the East Coast to become prevalent in the Northeast . It was not discovered in Southern California until 2001, then eradicated for over a decade; however, by 2011, it was again being found in Los Angeles County traps, then over the next two years expanded its range to Kern County and San Diego County . As of 2013 [ update ] , North American land favoring the environmental conditions of the Asian tiger mosquito was expected to more than triple in size in the coming 20 years, especially in urban areas. As of 2017 [ update ] Aedes albopictus mosquitoes have been identified in 1,368 counties in 40 U.S states. A 2019 study in Nature Microbiology that modeled expansion of Aedes albopictus due to climate change, urbanization, and human movement found that the species would likely continue to spread throughout the coming decades. In Latin America, the Asian tiger mosquito was first discovered 1986 in Brazil and in 1988 in Argentina and Mexico , as well. Other parts of Latin America where the Asian tiger mosquito was discovered are the Dominican Republic in 1993, Bolivia , Cuba, Honduras , and Guatemala in 1995, El Salvador in 1996, Paraguay in 1999, Panama in 2002, and Uruguay and Nicaragua in 2003. In Africa, the species was first detected in 1990 in South Africa. In Nigeria , it has been domestic since at least 1991. It spread to Cameroon in 1999/2000, to the Bioko Island of Equatorial Guinea in 2001, and to Gabon in 2006. In the Middle East, the species was detected in Lebanon in 2003 and in Syria in 2005; the first record in Israel was published in 2003. Ae. albopictus can outcompete and even eradicate other species with similar breeding habitats from the very start of its dispersal to other regions and biotopes. In Kolkata , for example, it was observed in the 1960s that egg depositing containers were being settled by the Asian tiger mosquito in city districts where the malaria mosquito (genus Anopheles ) and yellow fever mosquito ( Aedes aegypti ) had both been eliminated by the application of DDT . This may be because primarily the inner walls of the houses were treated with DDT to kill the mosquitoes resting there and fight the malaria mosquito. The yellow fever mosquito also lingers particularly in the inside of buildings and would have been also affected. The Asian tiger mosquito rests in the vicinity of human dwellings would therefore have an advantage over the other two species. In other cases where the yellow fever mosquito was repressed by the Asian tiger mosquito, for instance in Florida, this explanation does not fit. Other hypotheses include competition in the larval breeding waters, differences in metabolism and reproductive biology, or a major susceptibility to sporozoans (Apicomplexa). Another species which was suppressed by the migrating Ae. albopictus was Ae. guamensis in Guam . The Asian tiger mosquito is similar, in terms of its close socialization with humans, to the common house mosquito ( Culex pipiens ). Among other differences in their biology, Culex pipiens prefers larger breeding waters and is more tolerant to cold. In this respect, no significant competition or suppression between the two species likely occurs. A possible competition among mosquito species that all lay their eggs in knotholes and other similar places ( Ae. cretinus , Ae. geniculatus , and Anopheles plumbeus ) has yet to be observed. [ citation needed ] In Europe, the Asian tiger mosquito apparently covers an extensive new niche. This means that no native, long-established species conflict with the dispersal of Ae. albopictus . [ citation needed ]Ae. albopictus is known to transmit pathogens and viruses, such as the yellow fever virus, dengue fever , Chikungunya fever, and Usutu virus . There is some evidence supporting the role of Ae. albopictus in the transmission of Zika virus , which is primarily transmitted by the related Ae. aegypti . The Asian tiger mosquito was responsible for the Chikungunya epidemic on the French Island La Réunion in 2005–2006. By September 2006, an estimated 266,000 people were infected with the virus, and 248 fatalities occurred on the island. The Asian tiger mosquito was also the transmitter of the virus in the first outbreak of Chikungunya fever on the European continent. This outbreak occurred in the Italian province of Ravenna in the summer of 2007, and infected over 200 people. Evidently, mutated strains of the Chikungunya virus are being directly transmitted through Ae. albopictus particularly well and in such a way that another dispersal of the disease in regions with the Asian tiger mosquito is feared. On the basis of experimental evidence and probability estimates, the likelihood of mechanical or biological transmission of HIV by insects is virtually nonexistent. The tiger mosquito is relevant to veterinary medicine. For example, tiger mosquitoes are transmitters of Dirofilaria immitis , a parasitic roundworm that causes heart failure in dogs and cats. Wolbachia infection are the most common infection in arthropods today, and over 40% of arthropods have contracted it. Wolbachia can be transmitted from parent to offspring or between breeding individuals. Wolbachia is easily transmitted within the Ae. albopictus mosquito due to the effects it has on fecundity in females. Once female Asian tiger mosquitos have contracted the infection, they produce more eggs, give birth more frequently, and live longer than uninfected females. In this way, Wolbachia provides a fitness advantage to the infected females and prevents uninfected females from reproducing. This allows control of the spread of diseases that many species carry by suppressing reproduction of the individuals with the harmful disease, but without the Wolbachia infection. Wolbachia can also be used to transfer certain genes into the population to further control the spread of diseases. In the natural environment, Wolbachia and the Asian tiger mosquito are in a symbiotic relationship, so both species benefit from each other and can evolve together. The relationship between Wolbachia and its host might not have always been mutualistic, as Drosophila populations once experienced decreased fecundity in infected females, suggesting that Wolbachia evolved over time so that infected individuals would actually reproduce much more. The mechanism by which Wolbachia is inherited through maternal heredity is called cytoplasmic incompatibility . This changes the gamete cells of males and females, making some individuals unable to mate with each other. Although little is known about why cytoplasmic incompatibility exists, Wolbachia infection creates a fitness advantage for infected females, as they can mate with either infected or uninfected males. Despite this, infected males cannot reproduce with uninfected females. Therefore, over time, a population exposed to Wolbachia transitions from a few infected individuals to all individuals becoming infected, as the males that cannot reproduce successfully do not contribute to future generations. This is called population replacement, where the population's overall genotype is replaced by a new genotype. This shows how populations of Asian tiger mosquitoes can vary in number of Wolbachia -infected individuals, based on how often the infection is transmitted. Due to Wolbachia's ability to transmit from one host to the next, it can change the average genotype of a population, potentially reducing the population's gene flow with other nearby populations. [ citation needed ] This type of cytoplasmic incompatibility where an infected male cannot reproduce successfully with an uninfected female is called unidirectional cytoplasmic incompatibility. It occurs because Wolbachia modifies the paternal chromosomes during sperm development, leading to complications for these offspring during embryonic development. Also, bidirectional cytoplasmic incompatibility occurs when an infected male carrying one strain of Wolbachia reproduces with an infected female carrying a different strain of Wolbachia . This also results in failed reproduction. Bidirectional cytoplasmic incompatibility also has evolutionary implications for populations of Ae. albopictus and other vectors of the infection. This is because bidirectional cytoplasmic incompatibility in Wolbachia creates unviable offspring, reducing gene flow between two populations, which can eventually lead to speciation . [ citation needed ]Ae. albopictus is known to transmit pathogens and viruses, such as the yellow fever virus, dengue fever , Chikungunya fever, and Usutu virus . There is some evidence supporting the role of Ae. albopictus in the transmission of Zika virus , which is primarily transmitted by the related Ae. aegypti . The Asian tiger mosquito was responsible for the Chikungunya epidemic on the French Island La Réunion in 2005–2006. By September 2006, an estimated 266,000 people were infected with the virus, and 248 fatalities occurred on the island. The Asian tiger mosquito was also the transmitter of the virus in the first outbreak of Chikungunya fever on the European continent. This outbreak occurred in the Italian province of Ravenna in the summer of 2007, and infected over 200 people. Evidently, mutated strains of the Chikungunya virus are being directly transmitted through Ae. albopictus particularly well and in such a way that another dispersal of the disease in regions with the Asian tiger mosquito is feared. On the basis of experimental evidence and probability estimates, the likelihood of mechanical or biological transmission of HIV by insects is virtually nonexistent. The tiger mosquito is relevant to veterinary medicine. For example, tiger mosquitoes are transmitters of Dirofilaria immitis , a parasitic roundworm that causes heart failure in dogs and cats. Wolbachia infection are the most common infection in arthropods today, and over 40% of arthropods have contracted it. Wolbachia can be transmitted from parent to offspring or between breeding individuals. Wolbachia is easily transmitted within the Ae. albopictus mosquito due to the effects it has on fecundity in females. Once female Asian tiger mosquitos have contracted the infection, they produce more eggs, give birth more frequently, and live longer than uninfected females. In this way, Wolbachia provides a fitness advantage to the infected females and prevents uninfected females from reproducing. This allows control of the spread of diseases that many species carry by suppressing reproduction of the individuals with the harmful disease, but without the Wolbachia infection. Wolbachia can also be used to transfer certain genes into the population to further control the spread of diseases. In the natural environment, Wolbachia and the Asian tiger mosquito are in a symbiotic relationship, so both species benefit from each other and can evolve together. The relationship between Wolbachia and its host might not have always been mutualistic, as Drosophila populations once experienced decreased fecundity in infected females, suggesting that Wolbachia evolved over time so that infected individuals would actually reproduce much more. The mechanism by which Wolbachia is inherited through maternal heredity is called cytoplasmic incompatibility . This changes the gamete cells of males and females, making some individuals unable to mate with each other. Although little is known about why cytoplasmic incompatibility exists, Wolbachia infection creates a fitness advantage for infected females, as they can mate with either infected or uninfected males. Despite this, infected males cannot reproduce with uninfected females. Therefore, over time, a population exposed to Wolbachia transitions from a few infected individuals to all individuals becoming infected, as the males that cannot reproduce successfully do not contribute to future generations. This is called population replacement, where the population's overall genotype is replaced by a new genotype. This shows how populations of Asian tiger mosquitoes can vary in number of Wolbachia -infected individuals, based on how often the infection is transmitted. Due to Wolbachia's ability to transmit from one host to the next, it can change the average genotype of a population, potentially reducing the population's gene flow with other nearby populations. [ citation needed ] This type of cytoplasmic incompatibility where an infected male cannot reproduce successfully with an uninfected female is called unidirectional cytoplasmic incompatibility. It occurs because Wolbachia modifies the paternal chromosomes during sperm development, leading to complications for these offspring during embryonic development. Also, bidirectional cytoplasmic incompatibility occurs when an infected male carrying one strain of Wolbachia reproduces with an infected female carrying a different strain of Wolbachia . This also results in failed reproduction. Bidirectional cytoplasmic incompatibility also has evolutionary implications for populations of Ae. albopictus and other vectors of the infection. This is because bidirectional cytoplasmic incompatibility in Wolbachia creates unviable offspring, reducing gene flow between two populations, which can eventually lead to speciation . [ citation needed ]In the natural environment, Wolbachia and the Asian tiger mosquito are in a symbiotic relationship, so both species benefit from each other and can evolve together. The relationship between Wolbachia and its host might not have always been mutualistic, as Drosophila populations once experienced decreased fecundity in infected females, suggesting that Wolbachia evolved over time so that infected individuals would actually reproduce much more. The mechanism by which Wolbachia is inherited through maternal heredity is called cytoplasmic incompatibility . This changes the gamete cells of males and females, making some individuals unable to mate with each other. Although little is known about why cytoplasmic incompatibility exists, Wolbachia infection creates a fitness advantage for infected females, as they can mate with either infected or uninfected males. Despite this, infected males cannot reproduce with uninfected females. Therefore, over time, a population exposed to Wolbachia transitions from a few infected individuals to all individuals becoming infected, as the males that cannot reproduce successfully do not contribute to future generations. This is called population replacement, where the population's overall genotype is replaced by a new genotype. This shows how populations of Asian tiger mosquitoes can vary in number of Wolbachia -infected individuals, based on how often the infection is transmitted. Due to Wolbachia's ability to transmit from one host to the next, it can change the average genotype of a population, potentially reducing the population's gene flow with other nearby populations. [ citation needed ]This type of cytoplasmic incompatibility where an infected male cannot reproduce successfully with an uninfected female is called unidirectional cytoplasmic incompatibility. It occurs because Wolbachia modifies the paternal chromosomes during sperm development, leading to complications for these offspring during embryonic development. Also, bidirectional cytoplasmic incompatibility occurs when an infected male carrying one strain of Wolbachia reproduces with an infected female carrying a different strain of Wolbachia . This also results in failed reproduction. Bidirectional cytoplasmic incompatibility also has evolutionary implications for populations of Ae. albopictus and other vectors of the infection. This is because bidirectional cytoplasmic incompatibility in Wolbachia creates unviable offspring, reducing gene flow between two populations, which can eventually lead to speciation . [ citation needed ]Ae. albopictus is very difficult to suppress or to control due to its remarkable ability to adapt to various environments, its close contact with humans, and its reproductive biology. [ citation needed ] The containment of infestations is generally effected by public health services through area-wide integrated control plans, which aim to reduce the nuisance perceived by populations and the risks of viraemic transmission. Such plans consist of different activities that include entomological surveillance, larvicide treatments in public and private areas, information campaigns, and treatments against adult mosquitoes in the zones affected by suspected cases of transmissible viruses. Efficient monitoring or surveillance is essential to prevent the spread and establishment of this species. In addition to the monitoring of ports, warehouses with imported plants, and stockpiles of tires, rest areas on highways and train stations should be monitored with appropriate methods. The control of Asian tiger mosquitoes begins with destroying the places where they lay their eggs, which are never far from where people are being bitten, since they are weak fliers, with only about a 180-metre (590 ft) lifetime flying radius. Puddles that last more than three days, sagging or plugged roof gutters, old tires holding water, litter, and any other possible containers or pools of standing water should be drained or removed. Bird baths, inlets to sewers and drainage systems holding stagnant water, flower pots, standing flower vases, knotholes, and other crevices that can collect water should be filled with sand or fine gravel to prevent mosquitoes from laying their eggs in them. [ citation needed ] Any standing water in pools, catchment basins, etc., that cannot be drained, or dumped, can be periodically treated with properly labeled insecticides or Bacillus thuringiensis israelensis (Bti), often formed into doughnut-shaped "mosquito dunks". Bti produces toxins which are effective in killing larvae of mosquitoes and certain other dipterans , while having almost no effect on other organisms. Bti preparations are readily available at farm, garden, and pool suppliers. [ citation needed ] Flowing water will not be a breeding spot, [ contradictory ] and water that contains minnows is not usually a problem, because the fish eat the mosquito larvae. [ citation needed ] Adult and nymphal dragonflies have been proposed as biological control of mosquito species. Dragonfly nymphs eat mosquito larvae, at least in laboratory conditions, though studies of wild dragonfly diets have not shown mosquitoes to be part of dragonfly nymph diets. A study of adult dragonfly diets in Europe showed that adult mosquitoes were not an important food source. In any case, an efficient surveillance is essential to monitor the presence of tiger mosquitoes and the effect of control programs. Ovitraps are normally used for the monitoring of Ae. albopictus . They are black water containers with floating Styrofoam blocks or small wooden paddles that are in contact with the surface of the water. Female tiger mosquitoes lay their eggs on these surfaces. Through the identification of these eggs or of the larvae that hatch from these eggs in the laboratory, the presence and abundance of mosquito species can be estimated. Versions of these traps with an adhesive film (sticky traps) that catch the egg-depositing mosquitoes make the analysis much easier and quicker, but are more complicated in terms of handling. The results of ovitraps are often variable and depend on the availability of alternative egg-depositing waters. Due to this, it is best to use them in large numbers and in conjunction with other monitoring methods. [ citation needed ] To date, few effective traps for adult Asian tiger mosquitoes are available. Those traps that catch other species of mosquitoes do not catch tiger mosquitoes efficiently. A form of an ovitrap called a lethal ovitrap mimics the breeding site for Ae. albopictus just like the monitoring tool, but it has the added benefit of containing chemicals that are toxic to the mosquitoes when they enter, but do not harm humans. These traps have had success in some countries to control Aedes mosquito populations. A new trap type has now been shown to catch significant numbers of Ae. albopictus . This device, with the help of a ventilator, produces an upward air current of ammonia , fatty acids , and lactic acids that takes a similar form and smell of a human body. With the addition of carbon dioxide , the efficacy of the trap is increased. This means a suitable tool is available for trapping adult tiger mosquitoes, and for example, examining the existence of viruses in the trapped mosquitoes. Previously, the mosquitoes had to be collected from volunteers to be studied, which is ethically questionable, especially during epidemics. Recent research also indicates this trap type may also have a use as a control tool; in a study in Cesena , Italy , the number of biting tiger mosquitoes was reduced in places where traps were installed. An amino acid substitution mutation – F1534C – is overwhelmingly the most common voltage-gated sodium channel in A. albopictus in Singapore . This channel being the target of pyrethroids , this is suspected to be a knockdown resistance ( kdr ) mutation, and that that is the reason for its prevalence. The control of Asian tiger mosquitoes begins with destroying the places where they lay their eggs, which are never far from where people are being bitten, since they are weak fliers, with only about a 180-metre (590 ft) lifetime flying radius. Puddles that last more than three days, sagging or plugged roof gutters, old tires holding water, litter, and any other possible containers or pools of standing water should be drained or removed. Bird baths, inlets to sewers and drainage systems holding stagnant water, flower pots, standing flower vases, knotholes, and other crevices that can collect water should be filled with sand or fine gravel to prevent mosquitoes from laying their eggs in them. [ citation needed ] Any standing water in pools, catchment basins, etc., that cannot be drained, or dumped, can be periodically treated with properly labeled insecticides or Bacillus thuringiensis israelensis (Bti), often formed into doughnut-shaped "mosquito dunks". Bti produces toxins which are effective in killing larvae of mosquitoes and certain other dipterans , while having almost no effect on other organisms. Bti preparations are readily available at farm, garden, and pool suppliers. [ citation needed ] Flowing water will not be a breeding spot, [ contradictory ] and water that contains minnows is not usually a problem, because the fish eat the mosquito larvae. [ citation needed ]Adult and nymphal dragonflies have been proposed as biological control of mosquito species. Dragonfly nymphs eat mosquito larvae, at least in laboratory conditions, though studies of wild dragonfly diets have not shown mosquitoes to be part of dragonfly nymph diets. A study of adult dragonfly diets in Europe showed that adult mosquitoes were not an important food source. In any case, an efficient surveillance is essential to monitor the presence of tiger mosquitoes and the effect of control programs. Ovitraps are normally used for the monitoring of Ae. albopictus . They are black water containers with floating Styrofoam blocks or small wooden paddles that are in contact with the surface of the water. Female tiger mosquitoes lay their eggs on these surfaces. Through the identification of these eggs or of the larvae that hatch from these eggs in the laboratory, the presence and abundance of mosquito species can be estimated. Versions of these traps with an adhesive film (sticky traps) that catch the egg-depositing mosquitoes make the analysis much easier and quicker, but are more complicated in terms of handling. The results of ovitraps are often variable and depend on the availability of alternative egg-depositing waters. Due to this, it is best to use them in large numbers and in conjunction with other monitoring methods. [ citation needed ] To date, few effective traps for adult Asian tiger mosquitoes are available. Those traps that catch other species of mosquitoes do not catch tiger mosquitoes efficiently. A form of an ovitrap called a lethal ovitrap mimics the breeding site for Ae. albopictus just like the monitoring tool, but it has the added benefit of containing chemicals that are toxic to the mosquitoes when they enter, but do not harm humans. These traps have had success in some countries to control Aedes mosquito populations. A new trap type has now been shown to catch significant numbers of Ae. albopictus . This device, with the help of a ventilator, produces an upward air current of ammonia , fatty acids , and lactic acids that takes a similar form and smell of a human body. With the addition of carbon dioxide , the efficacy of the trap is increased. This means a suitable tool is available for trapping adult tiger mosquitoes, and for example, examining the existence of viruses in the trapped mosquitoes. Previously, the mosquitoes had to be collected from volunteers to be studied, which is ethically questionable, especially during epidemics. Recent research also indicates this trap type may also have a use as a control tool; in a study in Cesena , Italy , the number of biting tiger mosquitoes was reduced in places where traps were installed. An amino acid substitution mutation – F1534C – is overwhelmingly the most common voltage-gated sodium channel in A. albopictus in Singapore . This channel being the target of pyrethroids , this is suspected to be a knockdown resistance ( kdr ) mutation, and that that is the reason for its prevalence. Although the Wolbachia infection is prevalent in arthropod species, especially the Asian tiger mosquito, it is a useful mechanism for inhibiting the spread of dengue . Ae. aegypti individuals, a close relative of Ae. albopictus , with an artificial Wolbachia infection, cannot transmit dengue, an infectious virus, but they can pass on the Wolbachia infection to other populations. This could lead to many more discoveries in disease control for Ae. albopictus and other mosquito species. In addition, due to the cytoplasmic incompatibility caused by Wolbachia , the artificial infection of males can serve as a biological control as they are unable to reproduce successfully with uninfected females (unidirectional CI). When artificially infected males are unable to reproduce, the population size can be controlled, thereby reducing the transmission of the harmful disease of interest. Artificial infection of males is achieved by the removal of cytoplasm from infected oocytes, which is then transferred into embryos prior to the blastoderm stage. [ citation needed ]

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Dengue fever

Dengue fever is a mosquito-borne tropical disease caused by dengue virus . It is frequently asymptomatic ; if symptoms appear they typically begin 3 to 14 days after infection. These may include a high fever , headache , vomiting , muscle and joint pains , and a characteristic skin itching and skin rash . Recovery generally takes two to seven days. In a small proportion of cases, the disease develops into severe dengue (previously known as dengue hemorrhagic fever or dengue shock syndrome) with bleeding , low levels of blood platelets , blood plasma leakage, and dangerously low blood pressure . Dengue virus has four confirmed serotypes ; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications. The symptoms of dengue resemble many other diseases including malaria , influenza , and Zika . Blood tests are available to confirm the diagnosis including detecting viral RNA , or antibodies to the virus. There is no specific treatment for dengue fever. In mild cases, treatment is focused on treating pain symptoms. Severe cases of dengue require hospitalisation; treatment of acute dengue is supportive and includes giving fluid either by mouth or intravenously . Dengue is spread by several species of female mosquitoes of the Aedes genus , principally Aedes aegypti . Infection can be prevented by mosquito elimination and the prevention of bites. Two types of dengue vaccine have been approved and are commercially available. Dengvaxia became available in 2016 but it is only recommended to prevent re-infection in individuals who have been previously infected. The second vaccine, Qdenga, became available in 2022 and is suitable for adults, adolescents and children from four years of age. The earliest descriptions of a dengue outbreak date from 1779; its viral cause and spread were understood by the early 20th century. Already endemic in more than one hundred countries, dengue is spreading from tropical and subtropical regions to the Iberian Peninsula and the southern states of the US, partly attributed to climate change. It is classified as a neglected tropical disease . During 2023, more than 5 million infections were reported, with more than 5,000 dengue-related deaths. As most cases are asymptomatic or mild, the actual numbers of dengue cases and deaths are under-reported. Typically, people infected with dengue virus are asymptomatic (80%) or have only mild symptoms such as an uncomplicated fever. Others have more severe illness (5%), and in a small proportion it is life-threatening. The incubation period (time between exposure and onset of symptoms) ranges from 3 to 14 days, but most often it is 4 to 7 days. The characteristic symptoms of mild dengue are sudden-onset fever, headache (typically located behind the eyes), muscle and joint pains, nausea, vomiting, swollen glands and a rash. If this progresses to severe dengue the symptoms are severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums or nose, fatigue, restlessness, blood in vomit or stool, extreme thirst, pale and cold skin, and feelings of weakness. The course of infection is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue , (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . The course of infection is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue , (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . Dengue virus (DENV) is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it's also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga . Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. Dengue virus (DENV) is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it's also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga . Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. The World Health Organization 's International Classification of Diseases divides dengue fever into two classes: uncomplicated and severe. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage. Severe dengue can develop suddenly, sometimes after a few days as the fever subsides. Leakage of plasma from the capillaries results in extreme low blood pressure and hypovolemic shock ; Patients with severe plasma leakage may have fluid accumulation in the lungs or abdomen , insufficient protein in the blood , or thickening of the blood . Severe dengue is a medical emergency which can cause damage to organs, leading to multiple organ failure and death. Mild cases of dengue fever can easily be confused with several common diseases including Influenza , measles , chikungunya , and zika . Dengue, chikungunya and zika share the same mode of transmission ( Aedes mosquitoes) and are often endemic in the same regions, so that it is possible to be infected simultaneously by more than one disease. For travellers, dengue fever diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics . Warning symptoms of severe dengue include abdominal pain, persistent vomiting, odema, bleeding, lethargy, and liver enlargement. Once again, these symptoms can be confused with other diseases such as malaria, gastroenteritis, leptospirosis, and typhus. Blood tests can be used to confirm a diagnosis of dengue. During the first few days of infection, enzyme-linked immunosorbent assay ( ELISA ) can be used to detect the NS1 antigen ; however this antigen is produced by all flaviviruses. Four or five days into the infection, it is possible to reliably detect anti-dengue IgM antibodies, but this does not determine the serotype. Nucleic acid amplification tests provide the most reliable method of diagnosis. As of March 2024, there is no specific antiviral treatment available for dengue fever. Most cases of dengue fever have mild symptoms, and recovery takes place in a few days. No treatment is required for these cases. Acetaminophen (Paracetamol, Tylenol ) may be used to relieve mild fever or pain. Other common pain relievers, including aspirin , ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve) should be avoided as they can increase the risk of bleeding complications. For moderate illness, those who can drink, are passing urine, have no warning signs and are otherwise reasonably healthy can be monitored carefully at home. Supportive care with analgesics, fluid replacement, and bed rest are recommended. Severe dengue is a life-threatening emergency, requiring hospitalization and potentially intensive care. Warning signs include dehydration , decreasing platelets and increasing hematocrit . Treatment modes include intravenous fluids, and transfusion with platelets or plasma. Most people with dengue recover without any ongoing problems. The risk of death among those with severe dengue is 0.8% to 2.5%, and with adequate treatment this is less than 1%. However, those who develop significantly low blood pressure may have a fatality rate of up to 26%. The risk of death among children less than five years old is four times greater than among those over the age of 10. Elderly people are also at higher risk of a poor outcome. As of March 2023, dengue is endemic in more than 100 countries with cases reported in every continent with the exception of Antarctica. The Americas, Southeast Asia and the Western Pacific regions are the most seriously affected. It is difficult to estimate the full extent of the disease, as many cases are mild and not correctly diagnosed. WHO currently estimates that 3.9 billion people are at risk of dengue infection. In 2013, it was estimated that 390 million dengue infections occur every year, with 500,000 of these developing severe symptoms and 25,000 deaths. Generally, areas where dengue is endemic have only one serotype of the virus in circulation. The disease is said to be hyperendemic in areas where more than one serotype is circulating; this increases the risk of severe disease on a second or subsequent infection. Infections are most commonly acquired in urban environments where the virus is primarily transmitted by the mosquito species Aedes aegypti . This species has adapted to the urban environment, is generally found close to human habitation, prefers humans as its host, and takes advantage of small bodies of standing water (such as tanks and buckets) in which to breed. In rural settings the virus is transmitted to humans by A. aegypti and other related mosquitoes such as Aedes albopictus . Both these species have expanding ranges. Dengue has increased in incidence in recent decades, with WHO recording a ten fold increase between 2010 and 2019 (from 500,000 to 5 million recorded cases). This increase is tied closely to the increasing range of Aedes mosquitoes, which is attributed to a combination of urbanization , population growth, and an increasingly warm climate . In endemic areas, dengue infections peak when rainfall is optimal for mosquito breeding. The disease infects all races, sexes, and ages equally. In endemic areas, the infection is most commonly seen in children who then acquire a lifelong partial immunity. The first historical record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (266–420) which referred to a "water poison" associated with flying insects. The principal mosquito vector of dengue, Aedes aegypti , spread out of Africa in the 15th to 19th centuries due to the slave trade and consequent expansion of international trading. There have been descriptions of epidemics of dengue-like illness in the 17th century, and it is likely that epidemics in Jakarta , Cairo , and Philadelphia during the 18th century were caused by dengue. It is assumed that dengue was constantly present in many tropical urban centres throughout the 19th and early 20th centuries, even though significant outbreaks were infrequent. The marked spread of dengue during and after the Second World War has been attributed partly to disruption caused by the war, and partly to subsequent urbanisation in south-east Asia. As novel serotypes were introduced to regions already endemic with dengue, outbreaks of severe disease followed. The severe hemorrhagic form of the disease was first reported in the Philippines in 1953; by the 1970s, it had become recognised as a major cause of child mortality in Southeast Asia. In Central and South America, the Aedes mosquito had been eradicated in the 1950s; however the eradication program was discontinued in the 1970s and the diesase re-established itself in the region during the 1980s, becoming hyperendemic and causing significant epidemics. Dengue has continued to increase in prevalence during the 21st century, as the mosquito vector continues to expand its range. This is attributed partly to continuing urbanisation, and partly to the impact of a warmer climate. The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga (in full kidingapopo , "disease caused by an evil spirit"). The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy , and the disease was known as "dandy fever". The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush , in a 1789 report of the 1780 epidemic in Philadelphia , due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only after 1828. Other historical terms include "breakheart fever" and "la dengue". Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga (in full kidingapopo , "disease caused by an evil spirit"). The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy , and the disease was known as "dandy fever". The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush , in a 1789 report of the 1780 epidemic in Philadelphia , due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only after 1828. Other historical terms include "breakheart fever" and "la dengue". Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". Research directions include dengue pathogenesis (the process by which the disease develops in humans), as well as the biology, ecology and behaviour of the mosquito vector. Improved diagnostics would enable faster and more appropriate treatment. Attempts are ongoing to develop an antiviral medicine targeting the NS3 or NS5 proteins. In addition to the two vaccines which are already available, several vaccine candidates are in development. Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus. Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months. International Anti-Dengue Day is observed every year on 15 June in a number of countries. The idea was first agreed upon in 2010 with the first event held in Jakarta , Indonesia, in 2011. Further events were held in 2012 in Yangon , Myanmar, and in 2013 in Vietnam . Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998. A National Dengue Day is held in India annually on 16 May. A study estimate that the global burden of dengue in 2013 amounted to US$8·9 billion. Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus. Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months. International Anti-Dengue Day is observed every year on 15 June in a number of countries. The idea was first agreed upon in 2010 with the first event held in Jakarta , Indonesia, in 2011. Further events were held in 2012 in Yangon , Myanmar, and in 2013 in Vietnam . Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998. A National Dengue Day is held in India annually on 16 May. A study estimate that the global burden of dengue in 2013 amounted to US$8·9 billion.

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Chikungunya

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Julie Ledgerwood

Osteopathic Medicine Immunology Julie E. Ledgerwood is an American allergist and immunologist , who is the chief medical officer and chief of the Clinical Trials Program at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health in Bethesda, Maryland . She is a Doctor of Osteopathic Medicine . Ledgerwood leads clinical trials and clinical collaborations for the VRC; and has served as principal investigator, protocol chair, or associate investigator for over 60 Phase 1-2b clinical trials studying vaccines and monoclonal antibodies targeting pathogens such as HIV , influenza , Ebola , malaria , Chikungunya , and Zika in over 13 countries. She led the first human trial aimed at testing a vaccine for Ebola virus and the first evaluation of mAb114 , a monoclonal antibody targeting Ebola. For the past 15 years, she has conducted research with numerous academic research teams and has led international vaccine research collaborations. Ledgerwood has authored textbook chapters and over 85 publications in peer-reviewed journals.Ledgerwood graduated from Phillips University in Enid, Oklahoma and received her Doctor of Osteopathic Medicine degree from the College of Osteopathic Medicine at Oklahoma State University Center for Health Sciences . From 1999 to 2002, Ledgerwood completed her medical residency in internal medicine at Johns Hopkins Bayview Medical Center in Baltimore, Maryland . In 2002, Ledgerwood joined NIAID as a clinical fellow in allergy and immunology. In 2003, she joined the VRC as a clinical investigator. Ledgerwood is board certified by the American Board of Allergy and Immunology. Her work has been covered extensively in lay and scientific media outlets, including NBC News , Politico , The Guardian , NPR , and The New York Times .

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Chikungunya

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2013–2014 chikungunya outbreak

North America Mexico United States ( Florida ) Central America Belize Costa Rica El Salvador Guatemala Honduras Nicaragua Panama The 2013–2014 chikungunya outbreak represented the first recorded outbreak of the disease outside of tropical Africa and Asia. In December 2013, the first locally transmitted case of chikungunya in the Americas was detected in Saint Martin . Shortly after the first case the disease began to spread rapidly throughout the Caribbean region. By the end of the year, it had spread to Martinique and Guadeloupe , with suspected cases in Saint Barthélemy . By the end of January 2014, cases had been confirmed in Saint Barthélemy, as well as the British Virgin Islands , Dominica , and French Guiana . On the basis of 4,000 confirmed cases and over 30,000 suspected cases, the Caribbean Public Health Agency (CARPHA) declared a Caribbean-wide epidemic of the virus in early May. By the end of May, four cases of chikungunya had been confirmed in Florida. By July 2014 there were an estimated 355,000 cases in the Caribbean. By August 2014, 25 Caribbean countries had confirmed at least one case. The epidemic was over by 2015.Chikungunya is an arbovirus common to tropical regions of Africa and Asia. It is spread to humans by Aedes mosquitoes (primarily Aedes aegypti ) that breed in stagnant water. The virus was first isolated in 1953, and likely first arose during the 1700s. Chikungunya is characterized by a sudden high fever and intense joint pain, between four and seven days after infection. It can also cause headaches, muscle pain, fatigue, and rashes. Most infected patients recover within 10 days, and deaths are rare. However, in some cases joint pain can linger for months or years. There is no vaccine or treatment for chikungunya and preventing its spread is difficult. Outbreaks are primarily dealt with through preventive measures, such as wearing long-sleeved clothing, and vector population control. In early December 2013, health officials confirmed two cases of locally transmitted chikungunya on the French half of Saint Martin . It was announced to the public on December 17, by which time 10 cases had been confirmed and many more suspected cases were undergoing lab tests. Vice President Guillaume Arnell declared that his country had an "obligation" to prevent the disease from spreading. "It started here so we have to contain it here", he said. Swift action was taken, and a Pan American Health Organization representative said she was satisfied by the response. Even so, there were 66 confirmed cases by the end of the month, including at least one case on the Dutch half of the island, and more than 180 suspected cases. The virus had also spread to Martinique (3 cases) and Guadeloupe (1 case) by the end of the year. In Saint Barthélemy , there were 21 suspected cases. Previously, chikungunya had not been found in the Americas. Although it had never previously been found, it was considered an emerging threat and preparations for its spread were underway by 2012. In July 2013, a Caribbean-wide virtual meeting was held to educate high-ranking medical personnel on how to detect the virus. It is unclear how the virus first spread to the Americas' mosquito population. By January 21, 2014, cases had been St. Barthelemy and the British Virgin Islands . Dominica and French Guiana both had one reported case due to travel in the affected islands. At the start of April, chikungunya was confirmed in the Dominican Republic . On 24 April, Saint Vincent and the Grenadines announced the island had three confirmed cases of chikungunya and an outbreak was officially declared. Two days later, Antigua and Barbuda announced its first confirmed case, on the island of Antigua. Four other cases were suspected. At the end of April, there were more than 4,100 probable cases of chikungunya across fourteen different Caribbean countries. In addition to thirteen island nations, the virus had been confirmed in French Guiana. Martinique, Guadeloupe, and St. Martin had the most reported cases. During the week of April 27, 2014, health officials from multiple agencies met in the Dominican Republic to discuss the outbreak. On May 1, the Caribbean Public Health Agency (CARPHA) declared a Caribbean-wide epidemic of the virus. The United States-based Centers for Disease Control and Prevention said it was "working with state health departments to increase awareness about chikungunya and to facilitate diagnostic testing" in preparation for possible introduction into South Florida . As of May 19, 2014, the Dominican Republic had over 32,000 reported cases of chikungunya, representing 68% of the total cases registered to date. By the end of May, four cases had been confirmed in Florida. Over 50,000 people were suspected to have contracted the virus in total. As of late September 2014, Health Minister Nancy Pérez of Venezuela stated that only 400 Venezuelans were infected with chikungunya while the Central University of Venezuela stated that there could be between 65,000 and 117,000 Venezuelans infected. The Venezuelan government has announced a three-stage plan to counter the outbreak, with Health Minister Pérez stating that the key function is to eliminate areas of mosquito breeding. By November 2014 most of the Caribbean Islands were affected and the Pan-American Health Organization reported about 800,000 suspected cases alone in the Caribbean. The epidemic was over by 2015. [ citation needed ]

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Health in Bangladesh

Bangladesh is one of the most populous countries in the world, as well as having one of the fastest growing economies in the world. Consequently, Bangladesh faces challenges and opportunities in regards to public health. A remarkable metamorphosis has unfolded in Bangladesh, encompassing the demographic, health, and nutritional dimensions of its populace. The Human Rights Measurement Initiative finds that Bangladesh is fulfilling 89.3% of what it should be fulfilling for the right to health based on its level of income. When looking at the right to health with respect to children, Bangladesh achieves 95.0% of what is expected based on its current income. In regards to the right to health amongst the adult population, the country achieves only 94.2% of what is expected based on the nation's level of income. Bangladesh falls into the "bad" category when evaluating the right to reproductive health because the nation is fulfilling only 78.8% of what the nation is expected to achieve based on the resources (income) it has available. To ensure equitable healthcare for every resident in Bangladesh, an extensive network of health services has been established. Infrastructure of healthcare facilities can be divided into three levels: medical universities, medical college hospitals, and specialty hospitals exist at the tertiary level. District hospitals, maternal and child welfare centers are considered to be on the secondary level. Upazila health complexes, union health & family welfare centers, and community clinics (lowest-level healthcare facilities) are the primary level healthcare providers. Various NGOs and private institutions also contribute to this intricate network. The total expenditure on healthcare as a percentage of Bangladesh's GDP was 2.48% in 2019. In the parliamentary budget of 2017–18, the budget that was set for the health sector was 16 thousand 203 crore 36 lakhs taka. There are 3 hospital beds per 10,000 people. The general government expenditure on healthcare as a percentage of total government expenditure was 7.9% as of 2009. Citizens pay most of their health care bills as the out-of-pocket expenditures as a percentage of private expenditure on health: 96.5%. The doctor to population ratio is 1:2,000 and the nurse to population ratio is 1:5,000 Hospitals in Bangladesh play a vital role in the country's healthcare system, providing essential medical services to the population. With a growing emphasis on improving healthcare infrastructure, Bangladesh has made significant progress in expanding access to hospital facilities across the country. According to the World Health Organization (WHO), as of 2021, there were approximately 5,146 hospitals in Bangladesh, including both public and private institutions. These hospitals offer a wide range of medical specialties and services, ranging from general healthcare to specialized treatments. The government has also implemented various initiatives to enhance hospital quality and promote patient safety. The availability of hospitals has contributed to improving healthcare outcomes and addressing the healthcare needs of the Bangladeshi population.Hospitals in Bangladesh play a vital role in the country's healthcare system, providing essential medical services to the population. With a growing emphasis on improving healthcare infrastructure, Bangladesh has made significant progress in expanding access to hospital facilities across the country. According to the World Health Organization (WHO), as of 2021, there were approximately 5,146 hospitals in Bangladesh, including both public and private institutions. These hospitals offer a wide range of medical specialties and services, ranging from general healthcare to specialized treatments. The government has also implemented various initiatives to enhance hospital quality and promote patient safety. The availability of hospitals has contributed to improving healthcare outcomes and addressing the healthcare needs of the Bangladeshi population.Population – 168. million Rural population – 70% Population density – (population/km2) 1,070/sqkm People below poverty line – 60% Population doubling rate – 25–30 years GDP (current US$)(billions) – 300 CDR – 5.35 /1000 Maternal mortality ratio – 176 /100000 IMR – 31 /1000 live births Under 5 MR – 38 /1000 live births Total fertility rate – 2.1 Life expectancy at birth – 71 (m) and 73 (f) Fully immunized children – 52%Population – 168. million Rural population – 70% Population density – (population/km2) 1,070/sqkm People below poverty line – 60% Population doubling rate – 25–30 years GDP (current US$)(billions) – 300 CDR – 5.35 /1000 Maternal mortality ratio – 176 /100000 IMR – 31 /1000 live births Under 5 MR – 38 /1000 live births Total fertility rate – 2.1 Life expectancy at birth – 71 (m) and 73 (f) Fully immunized children – 52%Due to a large population, Bangladesh faces a large burden of disease: Malnutrition and environmental sanitation problems add to this burden. Historically, communicable diseases formed the bulk of total diseases in developing and tropical countries such as Bangladesh. By 2015 via Millennium development Goals, where communicable diseases were targeted, Bangladesh attained almost significant control on communicable diseases. An expanded immunization program against nine major diseases (TB, tetanus, diphtheria, whooping cough, polio, hepatitis B, Haemophilus influenza type B, measles, rubella) was undertaken for implementation. Background: Tuberculosis is one of the most dangerous chronic infectious diseases in Bangladesh. It is the major public health problem in this country. Mycobacterium tuberculosis is a commonly responsible organism of tuberculosis. It is an airborne disease that spreads through the coughing of an infected person. This disease is more prone to slum dwellers living in unhygienic conditions. Tuberculosis mainly infects the lungs ( pulmonary tuberculosis ) with the symptoms of persistent cough, evening fever with sweating, chest pain, weakness, weight loss, hemoptysis , etc. But it can also infect the other parts of the body ( extrapulmonary tuberculosis ) like the brain, kidneys and bones. In most cases patients infected with tuberculosis have other concomitant infections. HIV is more common to them. Present TB status of Bangladesh: According to the WHO, 'Global TB Report 2017' total population was 165 million, Bangladesh is one of the world's 30 high TB burden countries and near about 59170 people died due to tuberculosis. The total estimated number of TB patients was 364000, among them male patients were recorded at 236000, and female patients was 128000. In 2017 the total case was notified 244201. The total new and relapse case was 242639. People are mainly suffering from pulmonary TB; it was 81% ( 197800 patients ) of notified cases. Still now, HIV is considered as the most deadly infectious disease all over the world. It suppresses the immune system of the body. So any kind of infection can be incubated into the body, HIV infected person can be easily infected by mycobacterium tuberculosis. TB with HIV patient: Still now, HIV is considered as the most deadly infectious disease all over the world. It suppresses the immune system of the body. So any kind of infection can be incubated into the body, HIV infected person can be easily infected by mycobacterium tuberculosis, it is HIV-TB co infection . In 2017, the estimated number of the patient with HIV positive status tuberculosis was 540. Patient with HIV positive status ( new and relapse case ) notified was 89, out of 540 HIV positive patients. Among 89 patient 84 patients took anti-retroviral therapy . Drug resistance: When micro-organism of TB causes resistance to isoniazid or/and rifampicin the most effective drugs of TB. If the organism causes resistance against both of the drugs then it is called multi-drug-resistant tuberculosis ( MDR-TB ). In 2017 the estimated number of MDR was 8400, among them 5800 cases was notified and 944 patients were confirmed by laboratory test and 920 patients started immediate treatment. If any patient develops resistance against isoniazid/rifampicin and one of the 2nd line antibiotic fluoroquinolones ( i.e. amikacin, kanamycin, or capreomycin ), it's called extreme drug resistance tuberculosis ( XDR-TB ). In 2017, 6 patients were confirmed XDR-TB by laboratory diagnosis and all of them started treatment instantly. As 31 December 2017, countrywide a total 6420 MDR-TB patients were enrolled for treatment including 920. Among 920 patients, 425 patients were in 24 month regimen and 495 patients were 9 months regimen Bangladesh combats with TB: Under Mycrobacterial Disease Control (MBDC) Unit of the Director-General Health Service (DGHS), National Tuberculosis Control Program (NTP) is working with a goal to eliminate tuberculosis from Bangladesh. The NTP adopted DOTS ( directly observed treatment, short-course ) strategy during the fourth Population and Health Plan (1992-1998) and implemented it at field level in November 1993. This strategy reduced TB cases significantly. The program achieved 70% new smear-positive case reduction in 2006 and treated 85% of them since 2003. This program has successfully treated 95% of bacteriologically confirmed new pulmonary cases registered in 2016. Table-1: Bangladesh Indicator in Line with End TB Strategy In 2015 the TB case was noted 225/ per 100000 patient and the Government of Bangladesh has taken the target of reduction of TB New cases 10/ per 100000 patients by 2035 that will be around 1650 cases. However, recent statistics shows that non-communicable disease burden has increased to 61% of the total disease burden due to epidemiological transition. According to National NCD Risk Factor Survey in 2010, 99% of the survey population revealed at least one NCD risk factor and ≈29% showed >3 risk factors .Social transition, rapid urbanization and unhealthy dietary habit are the major stimulating reasons behind high prevalence of non-communicable diseases in Bangladesh remarkably in under-privileged communities such as rural inhabitants, urban slum dwellers. Diabetes, one of four priority non-communicable diseases targeted by world leaders has become a major health problem globally (537 million adults with diabetes in 2021 and projected to increase to 642 million by 2040). High fasting plasma glucose ranks seventh among risk factors for disease in South Asia. Bangladesh has the eighth highest population of people with diabetes, at 13.1 million. Studies have shown that the prevalence of diabetes is increasing moderately to significantly in the rural population of Bangladesh. However, compared to Western nations, the major diabetic population is non-obese. The prevalence of Diabetic retinopathy in Bangladesh is about one third of the total diabetic population (nearly 1.85 million) .These recent estimates are higher like western Countries and similar to Asian Malays living in Singapore. Sharp economic transition, urbanization, technology based modern life style, tight diabetes control guidelines and unwillingness to receive health care are thought to be the risk factors of diabetic retinopathy in Bangladesh. Unfortunately to attain that emerging health problem, the current capacity in the country to diagnose and treat diabetic retinopathy is very limited to a few centers. Till this year (2016), as per record of National Eye Care under HPNSDP (Health Population Nutrition Sector Development Program), 10,000 people with Diabetic Retinopathy have received services from Secondary and tertiary Hospitals where the screening programs have been established. Musculoskeletal disorders (MSDs) are a combination of inflammatory and degenerative conditions that influence the muscles, tendons, ligaments, joints or peripheral nerves, normally leading to aches, pains or discomfort. These are the most usual cause of severe long-term pain , physical disability and premature deaths. MSDs are one of the most prevalent occupational diseases liable for work limitation and absenteeism . Besides, these diseases can manifest as acute or chronic problems and can be incapacitating for their patients leading to huge costs for health systems particularly for chronic. pain. The causes of MSDs can be exposure to work-related or ergonomic risk factors and individual related risk factors. Repeated manual labor, lifting heavy loads, prolonged static work, overexertion, vibration, or working in an awkward posture usually leads work related MSDs. Extended working hours and uncomfortable postures were significantly associated with the risk of MSDs and workers who work for conventional working hours (8 hrs per day) were less prone to develop MSDs. Among Ready Made Garments workers lower back and upper back are the most affected area due to prolonged work and wrong posture. Moreover, work breaks, working under pressure or with deadlines, poor job design, job insecurity, and lack of social support from colleagues and supervisors are directly related to stress, and that stress can appear in increased muscle tension and other stress-related differences to the body, making workers more vulnerable to developing MSDs. Workers often work for extended hours in awkward position can also suffer MSDs. Age, gender, health and lifestyle are the individual risk factors that are responsible for the higher risk of MSDs and other chronic conditions . Person's skills and functions are affected by Musculoskeletal disorders and therefore influence their activities of daily life . Back and neck pain, osteoarthritis , rheumatoid arthritis and fractures are the most disabling conditions. Moreover, these are often correlated with major non-communicable co-morbidities (ischemic heart disease, stroke, cancer and chronic respiratory disease) and they jointly increase disabilities and deaths. The most prevalent MSDs in Bangladesh is low back pain (18.6%). Rapid urbanization, transition to sedentary work, weight gain; domestic and professional activities in banding posture may be responsible for the higher prevalence of low back pain in Bangladesh. The second commonest MSDs are knee osteoarthritis (7.3%) and it is related to more knee usage during occupational and household chores in Bangladesh. Besides these soft tissue injuries and rheumatism can be the third commonest disorders (3.8%) Among the female readymade garment workers in Bangladesh, the prevalence of lower back pain (41%) was the most leading accompanied by pain in the knees(33%) and neck pain (28%). Musculoskeletal disorders are mostly preventable and prevention is the best treatment. Therefore, understanding what these disorders are and the risk factors that contribute to their development is very fundamental. Furthermore, developing an effective and efficient prevention strategy requires, risk assessment process and implementation of technical, organizational, and person-oriented measures. According to WHO, "mental health is a state of well-being in which the individual realizes his or her own abilities, can cope with the normal stresses of life, can work productively and fruitfully, and is able to make a contribution to his or her community." The most difficult problem to tackle in this country is perhaps the environmental sanitation problem which is multi-faceted and multi-factorial. The twin problems of environmental sanitation are lack of safe drinking water in many areas of the country and preventive methods of excreta disposal. [ citation needed ] Bangladesh suffers from some of the most severe malnutrition problems. The present per capita intake is only 1850 kilocalorie which is by any standard, much below the required need. Malnutrition results from the convergence of poverty, inequitable food distribution, disease, illiteracy, rapid population growth and environmental risks, compounded by cultural and social inequities. Severe undernutrition exists mainly among families of landless agricultural labourers and farmers with a smallholding . [ citation needed ] Specific nutritional problems in the country are: [ citation needed ] Child malnutrition in Bangladesh is amongst the highest in the world. Two-thirds of the children under the age of five are under-nourished and about 60% of children under age six, are stunted. As of 1985, more than 45 percent of rural families and 76 percent of urban families were below the acceptable caloric intake level. Malnutrition is passed on through generations as malnourished mothers give birth to malnourished children. About one-third of babies in Bangladesh are born with low birth weight, increasing infant mortality rate, and an increased risk of diabetes and heart ailments in adulthood. One neonate dies in Bangladesh every three to four minutes; 120 000 neonates die every year. The World Bank estimates that Bangladesh is ranked 1st in the world of the number of children suffering from malnutrition. In Bangladesh, 26% of the population are undernourished and 46% of the children suffers from moderate to severe underweight problem. 43% of children under 5 years old are stunted. One in five preschool age children are vitamin A deficient and one in two are anaemic. Women also suffer most from malnutrition. To provide their family with food they pass on quality food which are essential for their nutrition. Most terrain of Bangladesh is low-lying and is prone to flooding. A large population of the country lives in areas that are at risk of experiencing extreme annual flooding that brings large destruction to the crops. Every year, 20% to 30% of Bangladesh is flooded. Floods threaten food security and their effects on agricultural production cause food shortage. The health and sanitation environment also affects malnutrition. Inadequacies in water supply, hygiene and sanitation have direct impacts on infectious diseases, such as malaria, parasitic diseases, and schistosomiasis . People are exposed to both water scarcity and poor water quality. Groundwater is often found to contain high arsenic concentration. Sanitation coverage in rural areas was only 35% in 1995. Almost one in three people in Bangladesh defecates in the open among the poorest families. Only 32% of the latrines in rural areas attain the international standards for a sanitary latrine. People are exposed to feces in their environment daily. The immune system falls and the disease processes exacerbate loss of nutrients, which worsens malnutrition. The diseases also contribute through the loss of appetite, lowered absorption of vitamins and nutrients, and loss of nutrients through diarrhoea or vomiting. Unemployment and job problems also lead to malnutrition in Bangladesh. In 2010, the unemployment rate was 5.1%. [ unreliable source? ] People do not have working facilities all year round and they are unable to afford the minimum cost of a nutritious diet due to the unsteady income. Undernourished mothers often give birth to infants who will have difficulty with development, pertaining to health problems such as wasting, stunting, underweight, anaemia, night blindness and iodine deficiency. As a result, Bangladesh has a high child mortality rate and is ranked 57 in the under-5 mortality rank. As 40% of the population in Bangladesh are children, malnutrition and its health effects among children can potentially lead to a lower educational attainment rate. Only 50% of an age group of children in Bangladesh managed to enroll into secondary school education. This would result in a low-skilled and low productivity workforce which would affect the economic growth rate of Bangladesh with only 3% GDP growth in 2009. Many programmes and efforts have been implemented to solve the problem of malnutrition in Bangladesh. UNICEF together with the government of Bangladesh and many other NGOs such as Helen Keller International , focus on improving the nutritional access of the population throughout their life-cycle from infants to the child-bearing mother. The impacts of the intervention are significant. Night blindness has reduced from 3.76% to 0.04% and iodine deficiency among school-aged children has decreased from 42.5% to 33.8%. Maternal and child health is an important issue in a country like Bangladesh . Bangladesh is one of the developing countries who signed onto achieving the Sustainable Development Goals (SDGs). In the new target of SDGs the issue of maternal and child health is fitting under goal number three. Over the last two decades, national health policy and strategies progressed with significant achievements. Still now Bangladesh is aiming to reduce maternal and child mortality through its renovation process. The MDG Goal five target was to reduce the maternal mortality rate (MMR) from 574 to 143 deaths per 100,000 live births by 2015 in Bangladesh. There has been a significant downfall in the MMR rates; however, the trajectory is not enough to meet the targets. The maternal mortality rate (MMR) per 100,000 live births was estimated at 385 globally and 563 in Bangladesh in 1990. In 2015, MMR was 176 per 100,00 live births in Bangladesh and 216 globally. However, the number of deaths of women while pregnant or within 42 days of termination of the pregnancy in Bangladesh were 21,000 in 1990 which reduced dramatically and reached at 5,500 in 2015. The reduction in maternal mortality is attributed to multiple factors. The factors like improved assess and utilization of health facilities, improvements in female education and per capita income helped to achieve the goal. Fertility reduction have also contributed to reduce MMR by lowering the number of high risk, high parity births. However, the antenatal care (ANC) coverage has been increased between 1990 and 2014. The proportion of women receiving at least one antenatal visit rose from 28% in 1990 to 64% in 2014 from a medically trained provider. In 2014, the population of women aged 15–49 who received postnatal care within 2 days after giving birth was 36%, antenatal coverage for at least four visits was 31%, proportion of births attended by skilled health personnel was 42%, caesarean section was 23%, proportion of women age 20–24 years old who gave birth before 18 years was 36%, number of women age 15–49 years with a live birth delivery in a health facility was 37% and births who had their first postnatal check-up within the first two days after birth was 31% in Bangladesh. The major causes of Maternal Mortality are - postpartum haemorrhage (31%), Eclampsia /pre-eclampsia (20%), delayed & obstructed labour (7%), Abortion (1%), other direct cause (5%) and indirect cause (35%). In Bangladesh prevalence of undernourishment among adolescent girls and pregnant women is very high, and one-third of such women have low BMI and anemia . In urban area, anemia and Vitamin A deficiency was found to be prevalent among most of the pregnant mothers. To achieve the MDG-4 target, Bangladesh has experienced a significant reduction of child mortality over the past decades. But under 5 mortality must be reduced to achieve the SDG Goal three target. Neonatal mortality is a puissant part of overall child mortality. Neonatal mortality rate of Bangladesh fell gradually from 1990 to 2015. In 1990, per 1000 live births under five mortality rate and infant mortality rate was 93 and 64 globally but in Bangladesh it was higher than the global average. In 2017, global under five mortality rate and infant mortality rate was 39 and 29 per 1000 live births respectively and in Bangladesh this rate was lower than the world average. In 1990, the number of under-5 deaths, infant deaths, and neonatal deaths were 532193.00, 368085.00 and 240316.00 and in 2017 the number reduced and reached at 99608.00, 82240.00 and 56341.00 respectively. The major causes of under-5 child mortality were preterm birth 18%, intrapartum 13.8%, pneumonia 13.5%, sepsis 11%, congenital 9.1%, injury 7.9%, diarrhoea 7.1%, measles 1.9% and other 15.9%. A study on risk factors of infant mortality, using data from the 2014 Bangladesh Demographic and Health Survey, showed that the risk of mortality in Bangladesh is 1.5 times higher for smaller babies. Infant mortality in Bangladesh is also lower for the urban population as well as for higher economic classes (which have greater access to health services). In Bangladesh, just over half of all children were anemic in 2011. A number of interventions have taken to address this issue, including the distribution of iron supplements and deworming tablets every 6 months till 5 years of age. However, children age 6–59 months receive Vitamin-A capsules twice a year. Between 2004 and 2014 the prevalence of children who are stunted, and underweight declined 29% and 23% respectively. But the prevalence of wasting showed very little change during this period. In the health system of Bangladesh, maternal and Child Health (MCH) services have been given highest priority. At the society level, MCH services are provided by the Family Welfare Assistants and Health Assistants . A Family Welfare Visitor (FWV) along with a Sub‑Assistant Community Medical Officer or Medical Assistants are responsible for providing the services, at the union level. At Upazila level, Medical officer provides MCH services in Upazila Health Complex. The activities of the Maternal and Child Health unit along with other maternal health care services are overseen by Upazila Health and Family Planning Officer in the Upazila Health Complex. The district hospitals provide maternal services through an outpatient consultation center and a labor ward. However, to provide MCH services private sector is playing supplementary and often competitive role in health sector with public one. NGOs also have a significant role providing primary, reproductive and family planning services. Union Ward Union Health and Family Welfare Centres Community Clinic In following decades, Bangladesh government's policy concentrated on reduction of population growth ; policy perceived that a consistent maternal and child health based family planning programme would help to achieve development goals. The Health and Population Sector Strategy (HPSS) was developed in 1997. The following seven strategies were included in the HPSP (MOHFW, 1998): 1) Focus on Emergency Obstetric Care for reducing maternal mortality, 2) Provision of Essential Obstetric Care/Basic maternity care services for promotion of "good practices" including early detection and appropriate referral of complications 3) Addressing the needs of women through a woman friendly hospital initiative 4) Communication for behaver change and development 5) Involvement of professional bodies 6) Stakeholder participation 7) Promotion of innovation. This policy document is theoretical framework of what is necessary and expected for improvement of maternal health situation in national level and It includes maternal services such as emergency obstetric care, antenatal care, skilled attendance, postnatal care, neonatal care and family planning. Occupational health deals with all aspects of health and safety in the workplace and has a strong focus on primary prevention of hazards . Bangladesh has emerged as a key player in RMG ( Ready Made Garment ) sector since 1978. Textiles and clothing account for about 85% of total export earnings of Bangladesh. Before the starting of RMG sector, woman's participation in the formal economy has been low compared to man but in late 1980s after orienting this sector, the scenario has dramatically changed and now 80 percent of the total employment in RMG sector is occupied by female worker. But the health of this 'women-driven sector' is neglected. Bangladesh has made significant progress in reducing maternal mortality . However, the work environment of RMG has the potential to create health problems, particularly for vulnerable groups such as pregnant women. This paper explores perceptions of health problems during pregnancy of factory workers, in this important industry in Bangladesh. Female workers reported that participation in paid work created an opportunity for them to earn money but pregnancy and the nature of the job, including being pressured to meet the production quota , pressure to leave the job because of their pregnancy and withholding of maternity benefits, cause stress, anxiety and may contribute to hypertensive disorders of pregnancy . This was confirmed by factory doctors who suggested that developing hypertensive disorders during pregnancy was influenced by the nature of work and stress . The employers seemed focused on profit and meeting quotas and the health of pregnant workers appeared to be a lower priority. The women reported that they do not visit the factory doctor for an ante-natal check-up when they first suspect that they are pregnant because they feel they need to hide their pregnancy from their supervisors. For example, they needs to meet a production quota of one hundred pieces per hour. If they lag behind the quota due to their pregnancy, their supervisors will encourage them to leave the job. They will also not be assigned to do overtime to earn extra money. They only go to the factory clinic for a check-up during pregnancy when their pregnancy becomes visible. They also do not go to the private clinics because of the cost. Doctor's room: Sickness Analysis Medical Issue Register Treatment Register Medicine Stock Register First Aid Training register Accident / injury Register Maternity Follow up file Medical Consolation Graph Maintain first aid kit The use of illegal drugs or the use of prescription or over-the-counter drugs or alcohol for purposes other than those for which they are meant to be used, or in excessive amounts. Different types of social, physical, emotional, and job-related problems can arise from substance abuse. This has become a matter of headache in recent years with overuse of substances like tobacco, alcohol, yaba along with some other prescribed drugs like sedatives or drugs used for anxiety disorders. Risk factors can influence drug abuse in several ways. The more risks a child is exposed to, the more likely the child will abuse drugs. Some risk factors may be more powerful than others at certain stages in development, such as peer pressure during the teenage years; just as some protective factors, such as a strong parent-child bond, can have a greater impact on reducing risks during the early years. An important goal of prevention is to change the balance between risk and protective factors so that protective factors outweigh risk factors. Table 1- Risk Factors and Protective Factors of Substance Abuse. Table 2- Prevalence of Alcohol and Drug use disorders. Approximately 126,000 deaths accounting for 13.5% of deaths were caused by tobacco from any cause in Bangladesh in 2018. Nearly 1.5 million adults were suffering from diseases attributable to tobacco use and due to exposure to secondhand smoke around 61,000 children were suffering from diseases. The direct healthcare costs attributable to tobacco use amounted to BDT 83.9 billion annually and the annual productivity loss, due to morbidity and premature mortality from tobacco-related diseases, was estimated to be BDT 221.7 billion. Thus, the total annual economic cost amounted to BDT 305.6 billion ($3.61 billion) which is equivalent to 1.4% of the GDP of Bangladesh in 2017–18. Smoking increases the risk of cancer, heart disease, stroke, lung diseases, diabetes, chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, tuberculosis, certain eye diseases and problems of the immune system, including rheumatoid arthritis. In Bangladesh, an alcoholic beverage is defined as any liquor with an alcohol content of ≥0.5%. These alcoholic beverages include beer (5% alcohol in volume), wine (12% alcohol in volume), spirits (40% alcohol in volume) and locally made alcoholic beverages (variable alcohol content). Locally produced alcoholic beverages are made from sorghum, maize, millet, rice, cider, fruit wine or fortified wine ( tari , bangle mod , haria , choani , do chuani , mohua , etc.). Though alcohol use is low in Bangladesh, those who use alcohol frequently binge drink, which is a public health concern. The use is prevalent among men, younger age groups, labourers, salaried government and nongovernment employees and businessmen, current smokers and those with a minimal educational background. Harmful use of alcohol is increasingly becoming a national concern as very few people with alcohol problems seek de-addiction treatment in Bangladesh. Injuries including motor vehicle crashes, falls, drownings, and burns Violence (homicide, suicide, sexual assault, and intimate partner violence) Alcohol poisoning Risky sexual behaviors such as unprotected sex or sex with multiple partners which may result in unintended pregnancy or sexually transmitted diseases Miscarriage and stillbirth or fetal abnormality. High blood pressure, heart disease, stroke, liver disease Learning and memory problem along with social problems Alcohol dependence etc. The main groups of illicit drugs used in international statistics are opioids, cocaine, amphetamines and cannabis. However, there is a range of other illicit drugs included in international drug control treaties. Deaths from drug use are of two types: – direct deaths which result from illicit drug overdoses. – indirect deaths resulting from illicit drug use acting as a risk factor for the development of various diseases and injury. Table 3- Deaths due to Illicit Drug Abuse. Death Weakened immune system, increasing the risk of illness and infection Heart conditions ranging from abnormal heart rates to heart attacks and collapsed veins and blood vessel infections from injected drugs Nausea, abdominal pain, changes in appetite and weight loss Liver damage or liver failure Seizures, stroke, mental confusion and brain damage Lung disease Problems with memory, attention and decision-making Behavioral problems including paranoia, aggressiveness, hallucination, addiction, impulsiveness, loss of self-control etc. Previously Bangladesh had no adequate and enabling law to handle the condition created by drug abuse and the related issues.The Government of the People's Republic of Bangladesh enacted the Narcotics Control Act in 1990 annulling all the colonial laws with a view to encountering drug problem true to the aspiration of the society. Historically, communicable diseases formed the bulk of total diseases in developing and tropical countries such as Bangladesh. By 2015 via Millennium development Goals, where communicable diseases were targeted, Bangladesh attained almost significant control on communicable diseases. An expanded immunization program against nine major diseases (TB, tetanus, diphtheria, whooping cough, polio, hepatitis B, Haemophilus influenza type B, measles, rubella) was undertaken for implementation. Background: Tuberculosis is one of the most dangerous chronic infectious diseases in Bangladesh. It is the major public health problem in this country. Mycobacterium tuberculosis is a commonly responsible organism of tuberculosis. It is an airborne disease that spreads through the coughing of an infected person. This disease is more prone to slum dwellers living in unhygienic conditions. Tuberculosis mainly infects the lungs ( pulmonary tuberculosis ) with the symptoms of persistent cough, evening fever with sweating, chest pain, weakness, weight loss, hemoptysis , etc. But it can also infect the other parts of the body ( extrapulmonary tuberculosis ) like the brain, kidneys and bones. In most cases patients infected with tuberculosis have other concomitant infections. HIV is more common to them. Present TB status of Bangladesh: According to the WHO, 'Global TB Report 2017' total population was 165 million, Bangladesh is one of the world's 30 high TB burden countries and near about 59170 people died due to tuberculosis. The total estimated number of TB patients was 364000, among them male patients were recorded at 236000, and female patients was 128000. In 2017 the total case was notified 244201. The total new and relapse case was 242639. People are mainly suffering from pulmonary TB; it was 81% ( 197800 patients ) of notified cases. Still now, HIV is considered as the most deadly infectious disease all over the world. It suppresses the immune system of the body. So any kind of infection can be incubated into the body, HIV infected person can be easily infected by mycobacterium tuberculosis. TB with HIV patient: Still now, HIV is considered as the most deadly infectious disease all over the world. It suppresses the immune system of the body. So any kind of infection can be incubated into the body, HIV infected person can be easily infected by mycobacterium tuberculosis, it is HIV-TB co infection . In 2017, the estimated number of the patient with HIV positive status tuberculosis was 540. Patient with HIV positive status ( new and relapse case ) notified was 89, out of 540 HIV positive patients. Among 89 patient 84 patients took anti-retroviral therapy . Drug resistance: When micro-organism of TB causes resistance to isoniazid or/and rifampicin the most effective drugs of TB. If the organism causes resistance against both of the drugs then it is called multi-drug-resistant tuberculosis ( MDR-TB ). In 2017 the estimated number of MDR was 8400, among them 5800 cases was notified and 944 patients were confirmed by laboratory test and 920 patients started immediate treatment. If any patient develops resistance against isoniazid/rifampicin and one of the 2nd line antibiotic fluoroquinolones ( i.e. amikacin, kanamycin, or capreomycin ), it's called extreme drug resistance tuberculosis ( XDR-TB ). In 2017, 6 patients were confirmed XDR-TB by laboratory diagnosis and all of them started treatment instantly. As 31 December 2017, countrywide a total 6420 MDR-TB patients were enrolled for treatment including 920. Among 920 patients, 425 patients were in 24 month regimen and 495 patients were 9 months regimen Bangladesh combats with TB: Under Mycrobacterial Disease Control (MBDC) Unit of the Director-General Health Service (DGHS), National Tuberculosis Control Program (NTP) is working with a goal to eliminate tuberculosis from Bangladesh. The NTP adopted DOTS ( directly observed treatment, short-course ) strategy during the fourth Population and Health Plan (1992-1998) and implemented it at field level in November 1993. This strategy reduced TB cases significantly. The program achieved 70% new smear-positive case reduction in 2006 and treated 85% of them since 2003. This program has successfully treated 95% of bacteriologically confirmed new pulmonary cases registered in 2016. Table-1: Bangladesh Indicator in Line with End TB Strategy In 2015 the TB case was noted 225/ per 100000 patient and the Government of Bangladesh has taken the target of reduction of TB New cases 10/ per 100000 patients by 2035 that will be around 1650 cases. Background: Tuberculosis is one of the most dangerous chronic infectious diseases in Bangladesh. It is the major public health problem in this country. Mycobacterium tuberculosis is a commonly responsible organism of tuberculosis. It is an airborne disease that spreads through the coughing of an infected person. This disease is more prone to slum dwellers living in unhygienic conditions. Tuberculosis mainly infects the lungs ( pulmonary tuberculosis ) with the symptoms of persistent cough, evening fever with sweating, chest pain, weakness, weight loss, hemoptysis , etc. But it can also infect the other parts of the body ( extrapulmonary tuberculosis ) like the brain, kidneys and bones. In most cases patients infected with tuberculosis have other concomitant infections. HIV is more common to them. Present TB status of Bangladesh: According to the WHO, 'Global TB Report 2017' total population was 165 million, Bangladesh is one of the world's 30 high TB burden countries and near about 59170 people died due to tuberculosis. The total estimated number of TB patients was 364000, among them male patients were recorded at 236000, and female patients was 128000. In 2017 the total case was notified 244201. The total new and relapse case was 242639. People are mainly suffering from pulmonary TB; it was 81% ( 197800 patients ) of notified cases. Still now, HIV is considered as the most deadly infectious disease all over the world. It suppresses the immune system of the body. So any kind of infection can be incubated into the body, HIV infected person can be easily infected by mycobacterium tuberculosis. TB with HIV patient: Still now, HIV is considered as the most deadly infectious disease all over the world. It suppresses the immune system of the body. So any kind of infection can be incubated into the body, HIV infected person can be easily infected by mycobacterium tuberculosis, it is HIV-TB co infection . In 2017, the estimated number of the patient with HIV positive status tuberculosis was 540. Patient with HIV positive status ( new and relapse case ) notified was 89, out of 540 HIV positive patients. Among 89 patient 84 patients took anti-retroviral therapy . Drug resistance: When micro-organism of TB causes resistance to isoniazid or/and rifampicin the most effective drugs of TB. If the organism causes resistance against both of the drugs then it is called multi-drug-resistant tuberculosis ( MDR-TB ). In 2017 the estimated number of MDR was 8400, among them 5800 cases was notified and 944 patients were confirmed by laboratory test and 920 patients started immediate treatment. If any patient develops resistance against isoniazid/rifampicin and one of the 2nd line antibiotic fluoroquinolones ( i.e. amikacin, kanamycin, or capreomycin ), it's called extreme drug resistance tuberculosis ( XDR-TB ). In 2017, 6 patients were confirmed XDR-TB by laboratory diagnosis and all of them started treatment instantly. As 31 December 2017, countrywide a total 6420 MDR-TB patients were enrolled for treatment including 920. Among 920 patients, 425 patients were in 24 month regimen and 495 patients were 9 months regimen Bangladesh combats with TB: Under Mycrobacterial Disease Control (MBDC) Unit of the Director-General Health Service (DGHS), National Tuberculosis Control Program (NTP) is working with a goal to eliminate tuberculosis from Bangladesh. The NTP adopted DOTS ( directly observed treatment, short-course ) strategy during the fourth Population and Health Plan (1992-1998) and implemented it at field level in November 1993. This strategy reduced TB cases significantly. The program achieved 70% new smear-positive case reduction in 2006 and treated 85% of them since 2003. This program has successfully treated 95% of bacteriologically confirmed new pulmonary cases registered in 2016. Table-1: Bangladesh Indicator in Line with End TB Strategy In 2015 the TB case was noted 225/ per 100000 patient and the Government of Bangladesh has taken the target of reduction of TB New cases 10/ per 100000 patients by 2035 that will be around 1650 cases. However, recent statistics shows that non-communicable disease burden has increased to 61% of the total disease burden due to epidemiological transition. According to National NCD Risk Factor Survey in 2010, 99% of the survey population revealed at least one NCD risk factor and ≈29% showed >3 risk factors .Social transition, rapid urbanization and unhealthy dietary habit are the major stimulating reasons behind high prevalence of non-communicable diseases in Bangladesh remarkably in under-privileged communities such as rural inhabitants, urban slum dwellers. Diabetes, one of four priority non-communicable diseases targeted by world leaders has become a major health problem globally (537 million adults with diabetes in 2021 and projected to increase to 642 million by 2040). High fasting plasma glucose ranks seventh among risk factors for disease in South Asia. Bangladesh has the eighth highest population of people with diabetes, at 13.1 million. Studies have shown that the prevalence of diabetes is increasing moderately to significantly in the rural population of Bangladesh. However, compared to Western nations, the major diabetic population is non-obese. The prevalence of Diabetic retinopathy in Bangladesh is about one third of the total diabetic population (nearly 1.85 million) .These recent estimates are higher like western Countries and similar to Asian Malays living in Singapore. Sharp economic transition, urbanization, technology based modern life style, tight diabetes control guidelines and unwillingness to receive health care are thought to be the risk factors of diabetic retinopathy in Bangladesh. Unfortunately to attain that emerging health problem, the current capacity in the country to diagnose and treat diabetic retinopathy is very limited to a few centers. Till this year (2016), as per record of National Eye Care under HPNSDP (Health Population Nutrition Sector Development Program), 10,000 people with Diabetic Retinopathy have received services from Secondary and tertiary Hospitals where the screening programs have been established. Musculoskeletal disorders (MSDs) are a combination of inflammatory and degenerative conditions that influence the muscles, tendons, ligaments, joints or peripheral nerves, normally leading to aches, pains or discomfort. These are the most usual cause of severe long-term pain , physical disability and premature deaths. MSDs are one of the most prevalent occupational diseases liable for work limitation and absenteeism . Besides, these diseases can manifest as acute or chronic problems and can be incapacitating for their patients leading to huge costs for health systems particularly for chronic. pain. The causes of MSDs can be exposure to work-related or ergonomic risk factors and individual related risk factors. Repeated manual labor, lifting heavy loads, prolonged static work, overexertion, vibration, or working in an awkward posture usually leads work related MSDs. Extended working hours and uncomfortable postures were significantly associated with the risk of MSDs and workers who work for conventional working hours (8 hrs per day) were less prone to develop MSDs. Among Ready Made Garments workers lower back and upper back are the most affected area due to prolonged work and wrong posture. Moreover, work breaks, working under pressure or with deadlines, poor job design, job insecurity, and lack of social support from colleagues and supervisors are directly related to stress, and that stress can appear in increased muscle tension and other stress-related differences to the body, making workers more vulnerable to developing MSDs. Workers often work for extended hours in awkward position can also suffer MSDs. Age, gender, health and lifestyle are the individual risk factors that are responsible for the higher risk of MSDs and other chronic conditions . Person's skills and functions are affected by Musculoskeletal disorders and therefore influence their activities of daily life . Back and neck pain, osteoarthritis , rheumatoid arthritis and fractures are the most disabling conditions. Moreover, these are often correlated with major non-communicable co-morbidities (ischemic heart disease, stroke, cancer and chronic respiratory disease) and they jointly increase disabilities and deaths. The most prevalent MSDs in Bangladesh is low back pain (18.6%). Rapid urbanization, transition to sedentary work, weight gain; domestic and professional activities in banding posture may be responsible for the higher prevalence of low back pain in Bangladesh. The second commonest MSDs are knee osteoarthritis (7.3%) and it is related to more knee usage during occupational and household chores in Bangladesh. Besides these soft tissue injuries and rheumatism can be the third commonest disorders (3.8%) Among the female readymade garment workers in Bangladesh, the prevalence of lower back pain (41%) was the most leading accompanied by pain in the knees(33%) and neck pain (28%). Musculoskeletal disorders are mostly preventable and prevention is the best treatment. Therefore, understanding what these disorders are and the risk factors that contribute to their development is very fundamental. Furthermore, developing an effective and efficient prevention strategy requires, risk assessment process and implementation of technical, organizational, and person-oriented measures. According to WHO, "mental health is a state of well-being in which the individual realizes his or her own abilities, can cope with the normal stresses of life, can work productively and fruitfully, and is able to make a contribution to his or her community." The most difficult problem to tackle in this country is perhaps the environmental sanitation problem which is multi-faceted and multi-factorial. The twin problems of environmental sanitation are lack of safe drinking water in many areas of the country and preventive methods of excreta disposal. [ citation needed ] Bangladesh suffers from some of the most severe malnutrition problems. The present per capita intake is only 1850 kilocalorie which is by any standard, much below the required need. Malnutrition results from the convergence of poverty, inequitable food distribution, disease, illiteracy, rapid population growth and environmental risks, compounded by cultural and social inequities. Severe undernutrition exists mainly among families of landless agricultural labourers and farmers with a smallholding . [ citation needed ] Specific nutritional problems in the country are: [ citation needed ] Child malnutrition in Bangladesh is amongst the highest in the world. Two-thirds of the children under the age of five are under-nourished and about 60% of children under age six, are stunted. As of 1985, more than 45 percent of rural families and 76 percent of urban families were below the acceptable caloric intake level. Malnutrition is passed on through generations as malnourished mothers give birth to malnourished children. About one-third of babies in Bangladesh are born with low birth weight, increasing infant mortality rate, and an increased risk of diabetes and heart ailments in adulthood. One neonate dies in Bangladesh every three to four minutes; 120 000 neonates die every year. The World Bank estimates that Bangladesh is ranked 1st in the world of the number of children suffering from malnutrition. In Bangladesh, 26% of the population are undernourished and 46% of the children suffers from moderate to severe underweight problem. 43% of children under 5 years old are stunted. One in five preschool age children are vitamin A deficient and one in two are anaemic. Women also suffer most from malnutrition. To provide their family with food they pass on quality food which are essential for their nutrition. Most terrain of Bangladesh is low-lying and is prone to flooding. A large population of the country lives in areas that are at risk of experiencing extreme annual flooding that brings large destruction to the crops. Every year, 20% to 30% of Bangladesh is flooded. Floods threaten food security and their effects on agricultural production cause food shortage. The health and sanitation environment also affects malnutrition. Inadequacies in water supply, hygiene and sanitation have direct impacts on infectious diseases, such as malaria, parasitic diseases, and schistosomiasis . People are exposed to both water scarcity and poor water quality. Groundwater is often found to contain high arsenic concentration. Sanitation coverage in rural areas was only 35% in 1995. Almost one in three people in Bangladesh defecates in the open among the poorest families. Only 32% of the latrines in rural areas attain the international standards for a sanitary latrine. People are exposed to feces in their environment daily. The immune system falls and the disease processes exacerbate loss of nutrients, which worsens malnutrition. The diseases also contribute through the loss of appetite, lowered absorption of vitamins and nutrients, and loss of nutrients through diarrhoea or vomiting. Unemployment and job problems also lead to malnutrition in Bangladesh. In 2010, the unemployment rate was 5.1%. [ unreliable source? ] People do not have working facilities all year round and they are unable to afford the minimum cost of a nutritious diet due to the unsteady income. Undernourished mothers often give birth to infants who will have difficulty with development, pertaining to health problems such as wasting, stunting, underweight, anaemia, night blindness and iodine deficiency. As a result, Bangladesh has a high child mortality rate and is ranked 57 in the under-5 mortality rank. As 40% of the population in Bangladesh are children, malnutrition and its health effects among children can potentially lead to a lower educational attainment rate. Only 50% of an age group of children in Bangladesh managed to enroll into secondary school education. This would result in a low-skilled and low productivity workforce which would affect the economic growth rate of Bangladesh with only 3% GDP growth in 2009. Many programmes and efforts have been implemented to solve the problem of malnutrition in Bangladesh. UNICEF together with the government of Bangladesh and many other NGOs such as Helen Keller International , focus on improving the nutritional access of the population throughout their life-cycle from infants to the child-bearing mother. The impacts of the intervention are significant. Night blindness has reduced from 3.76% to 0.04% and iodine deficiency among school-aged children has decreased from 42.5% to 33.8%. Maternal and child health is an important issue in a country like Bangladesh . Bangladesh is one of the developing countries who signed onto achieving the Sustainable Development Goals (SDGs). In the new target of SDGs the issue of maternal and child health is fitting under goal number three. Over the last two decades, national health policy and strategies progressed with significant achievements. Still now Bangladesh is aiming to reduce maternal and child mortality through its renovation process. The MDG Goal five target was to reduce the maternal mortality rate (MMR) from 574 to 143 deaths per 100,000 live births by 2015 in Bangladesh. There has been a significant downfall in the MMR rates; however, the trajectory is not enough to meet the targets. The maternal mortality rate (MMR) per 100,000 live births was estimated at 385 globally and 563 in Bangladesh in 1990. In 2015, MMR was 176 per 100,00 live births in Bangladesh and 216 globally. However, the number of deaths of women while pregnant or within 42 days of termination of the pregnancy in Bangladesh were 21,000 in 1990 which reduced dramatically and reached at 5,500 in 2015. The reduction in maternal mortality is attributed to multiple factors. The factors like improved assess and utilization of health facilities, improvements in female education and per capita income helped to achieve the goal. Fertility reduction have also contributed to reduce MMR by lowering the number of high risk, high parity births. However, the antenatal care (ANC) coverage has been increased between 1990 and 2014. The proportion of women receiving at least one antenatal visit rose from 28% in 1990 to 64% in 2014 from a medically trained provider. In 2014, the population of women aged 15–49 who received postnatal care within 2 days after giving birth was 36%, antenatal coverage for at least four visits was 31%, proportion of births attended by skilled health personnel was 42%, caesarean section was 23%, proportion of women age 20–24 years old who gave birth before 18 years was 36%, number of women age 15–49 years with a live birth delivery in a health facility was 37% and births who had their first postnatal check-up within the first two days after birth was 31% in Bangladesh. The major causes of Maternal Mortality are - postpartum haemorrhage (31%), Eclampsia /pre-eclampsia (20%), delayed & obstructed labour (7%), Abortion (1%), other direct cause (5%) and indirect cause (35%). In Bangladesh prevalence of undernourishment among adolescent girls and pregnant women is very high, and one-third of such women have low BMI and anemia . In urban area, anemia and Vitamin A deficiency was found to be prevalent among most of the pregnant mothers. To achieve the MDG-4 target, Bangladesh has experienced a significant reduction of child mortality over the past decades. But under 5 mortality must be reduced to achieve the SDG Goal three target. Neonatal mortality is a puissant part of overall child mortality. Neonatal mortality rate of Bangladesh fell gradually from 1990 to 2015. In 1990, per 1000 live births under five mortality rate and infant mortality rate was 93 and 64 globally but in Bangladesh it was higher than the global average. In 2017, global under five mortality rate and infant mortality rate was 39 and 29 per 1000 live births respectively and in Bangladesh this rate was lower than the world average. In 1990, the number of under-5 deaths, infant deaths, and neonatal deaths were 532193.00, 368085.00 and 240316.00 and in 2017 the number reduced and reached at 99608.00, 82240.00 and 56341.00 respectively. The major causes of under-5 child mortality were preterm birth 18%, intrapartum 13.8%, pneumonia 13.5%, sepsis 11%, congenital 9.1%, injury 7.9%, diarrhoea 7.1%, measles 1.9% and other 15.9%. A study on risk factors of infant mortality, using data from the 2014 Bangladesh Demographic and Health Survey, showed that the risk of mortality in Bangladesh is 1.5 times higher for smaller babies. Infant mortality in Bangladesh is also lower for the urban population as well as for higher economic classes (which have greater access to health services). In Bangladesh, just over half of all children were anemic in 2011. A number of interventions have taken to address this issue, including the distribution of iron supplements and deworming tablets every 6 months till 5 years of age. However, children age 6–59 months receive Vitamin-A capsules twice a year. Between 2004 and 2014 the prevalence of children who are stunted, and underweight declined 29% and 23% respectively. But the prevalence of wasting showed very little change during this period. In the health system of Bangladesh, maternal and Child Health (MCH) services have been given highest priority. At the society level, MCH services are provided by the Family Welfare Assistants and Health Assistants . A Family Welfare Visitor (FWV) along with a Sub‑Assistant Community Medical Officer or Medical Assistants are responsible for providing the services, at the union level. At Upazila level, Medical officer provides MCH services in Upazila Health Complex. The activities of the Maternal and Child Health unit along with other maternal health care services are overseen by Upazila Health and Family Planning Officer in the Upazila Health Complex. The district hospitals provide maternal services through an outpatient consultation center and a labor ward. However, to provide MCH services private sector is playing supplementary and often competitive role in health sector with public one. NGOs also have a significant role providing primary, reproductive and family planning services. Union Ward Union Health and Family Welfare Centres Community Clinic In following decades, Bangladesh government's policy concentrated on reduction of population growth ; policy perceived that a consistent maternal and child health based family planning programme would help to achieve development goals. The Health and Population Sector Strategy (HPSS) was developed in 1997. The following seven strategies were included in the HPSP (MOHFW, 1998): 1) Focus on Emergency Obstetric Care for reducing maternal mortality, 2) Provision of Essential Obstetric Care/Basic maternity care services for promotion of "good practices" including early detection and appropriate referral of complications 3) Addressing the needs of women through a woman friendly hospital initiative 4) Communication for behaver change and development 5) Involvement of professional bodies 6) Stakeholder participation 7) Promotion of innovation. This policy document is theoretical framework of what is necessary and expected for improvement of maternal health situation in national level and It includes maternal services such as emergency obstetric care, antenatal care, skilled attendance, postnatal care, neonatal care and family planning. Occupational health deals with all aspects of health and safety in the workplace and has a strong focus on primary prevention of hazards . Bangladesh has emerged as a key player in RMG ( Ready Made Garment ) sector since 1978. Textiles and clothing account for about 85% of total export earnings of Bangladesh. Before the starting of RMG sector, woman's participation in the formal economy has been low compared to man but in late 1980s after orienting this sector, the scenario has dramatically changed and now 80 percent of the total employment in RMG sector is occupied by female worker. But the health of this 'women-driven sector' is neglected. Bangladesh has made significant progress in reducing maternal mortality . However, the work environment of RMG has the potential to create health problems, particularly for vulnerable groups such as pregnant women. This paper explores perceptions of health problems during pregnancy of factory workers, in this important industry in Bangladesh. Female workers reported that participation in paid work created an opportunity for them to earn money but pregnancy and the nature of the job, including being pressured to meet the production quota , pressure to leave the job because of their pregnancy and withholding of maternity benefits, cause stress, anxiety and may contribute to hypertensive disorders of pregnancy . This was confirmed by factory doctors who suggested that developing hypertensive disorders during pregnancy was influenced by the nature of work and stress . The employers seemed focused on profit and meeting quotas and the health of pregnant workers appeared to be a lower priority. The women reported that they do not visit the factory doctor for an ante-natal check-up when they first suspect that they are pregnant because they feel they need to hide their pregnancy from their supervisors. For example, they needs to meet a production quota of one hundred pieces per hour. If they lag behind the quota due to their pregnancy, their supervisors will encourage them to leave the job. They will also not be assigned to do overtime to earn extra money. They only go to the factory clinic for a check-up during pregnancy when their pregnancy becomes visible. They also do not go to the private clinics because of the cost. Doctor's room: Sickness Analysis Medical Issue Register Treatment Register Medicine Stock Register First Aid Training register Accident / injury Register Maternity Follow up file Medical Consolation Graph Maintain first aid kit The use of illegal drugs or the use of prescription or over-the-counter drugs or alcohol for purposes other than those for which they are meant to be used, or in excessive amounts. Different types of social, physical, emotional, and job-related problems can arise from substance abuse. This has become a matter of headache in recent years with overuse of substances like tobacco, alcohol, yaba along with some other prescribed drugs like sedatives or drugs used for anxiety disorders. Risk factors can influence drug abuse in several ways. The more risks a child is exposed to, the more likely the child will abuse drugs. Some risk factors may be more powerful than others at certain stages in development, such as peer pressure during the teenage years; just as some protective factors, such as a strong parent-child bond, can have a greater impact on reducing risks during the early years. An important goal of prevention is to change the balance between risk and protective factors so that protective factors outweigh risk factors. Table 1- Risk Factors and Protective Factors of Substance Abuse. Table 2- Prevalence of Alcohol and Drug use disorders. Approximately 126,000 deaths accounting for 13.5% of deaths were caused by tobacco from any cause in Bangladesh in 2018. Nearly 1.5 million adults were suffering from diseases attributable to tobacco use and due to exposure to secondhand smoke around 61,000 children were suffering from diseases. The direct healthcare costs attributable to tobacco use amounted to BDT 83.9 billion annually and the annual productivity loss, due to morbidity and premature mortality from tobacco-related diseases, was estimated to be BDT 221.7 billion. Thus, the total annual economic cost amounted to BDT 305.6 billion ($3.61 billion) which is equivalent to 1.4% of the GDP of Bangladesh in 2017–18. Smoking increases the risk of cancer, heart disease, stroke, lung diseases, diabetes, chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, tuberculosis, certain eye diseases and problems of the immune system, including rheumatoid arthritis. In Bangladesh, an alcoholic beverage is defined as any liquor with an alcohol content of ≥0.5%. These alcoholic beverages include beer (5% alcohol in volume), wine (12% alcohol in volume), spirits (40% alcohol in volume) and locally made alcoholic beverages (variable alcohol content). Locally produced alcoholic beverages are made from sorghum, maize, millet, rice, cider, fruit wine or fortified wine ( tari , bangle mod , haria , choani , do chuani , mohua , etc.). Though alcohol use is low in Bangladesh, those who use alcohol frequently binge drink, which is a public health concern. The use is prevalent among men, younger age groups, labourers, salaried government and nongovernment employees and businessmen, current smokers and those with a minimal educational background. Harmful use of alcohol is increasingly becoming a national concern as very few people with alcohol problems seek de-addiction treatment in Bangladesh. Injuries including motor vehicle crashes, falls, drownings, and burns Violence (homicide, suicide, sexual assault, and intimate partner violence) Alcohol poisoning Risky sexual behaviors such as unprotected sex or sex with multiple partners which may result in unintended pregnancy or sexually transmitted diseases Miscarriage and stillbirth or fetal abnormality. High blood pressure, heart disease, stroke, liver disease Learning and memory problem along with social problems Alcohol dependence etc. The main groups of illicit drugs used in international statistics are opioids, cocaine, amphetamines and cannabis. However, there is a range of other illicit drugs included in international drug control treaties. Deaths from drug use are of two types: – direct deaths which result from illicit drug overdoses. – indirect deaths resulting from illicit drug use acting as a risk factor for the development of various diseases and injury. Table 3- Deaths due to Illicit Drug Abuse. Death Weakened immune system, increasing the risk of illness and infection Heart conditions ranging from abnormal heart rates to heart attacks and collapsed veins and blood vessel infections from injected drugs Nausea, abdominal pain, changes in appetite and weight loss Liver damage or liver failure Seizures, stroke, mental confusion and brain damage Lung disease Problems with memory, attention and decision-making Behavioral problems including paranoia, aggressiveness, hallucination, addiction, impulsiveness, loss of self-control etc. Previously Bangladesh had no adequate and enabling law to handle the condition created by drug abuse and the related issues.The Government of the People's Republic of Bangladesh enacted the Narcotics Control Act in 1990 annulling all the colonial laws with a view to encountering drug problem true to the aspiration of the society. Diabetes, one of four priority non-communicable diseases targeted by world leaders has become a major health problem globally (537 million adults with diabetes in 2021 and projected to increase to 642 million by 2040). High fasting plasma glucose ranks seventh among risk factors for disease in South Asia. Bangladesh has the eighth highest population of people with diabetes, at 13.1 million. Studies have shown that the prevalence of diabetes is increasing moderately to significantly in the rural population of Bangladesh. However, compared to Western nations, the major diabetic population is non-obese. The prevalence of Diabetic retinopathy in Bangladesh is about one third of the total diabetic population (nearly 1.85 million) .These recent estimates are higher like western Countries and similar to Asian Malays living in Singapore. Sharp economic transition, urbanization, technology based modern life style, tight diabetes control guidelines and unwillingness to receive health care are thought to be the risk factors of diabetic retinopathy in Bangladesh. Unfortunately to attain that emerging health problem, the current capacity in the country to diagnose and treat diabetic retinopathy is very limited to a few centers. Till this year (2016), as per record of National Eye Care under HPNSDP (Health Population Nutrition Sector Development Program), 10,000 people with Diabetic Retinopathy have received services from Secondary and tertiary Hospitals where the screening programs have been established. Musculoskeletal disorders (MSDs) are a combination of inflammatory and degenerative conditions that influence the muscles, tendons, ligaments, joints or peripheral nerves, normally leading to aches, pains or discomfort. These are the most usual cause of severe long-term pain , physical disability and premature deaths. MSDs are one of the most prevalent occupational diseases liable for work limitation and absenteeism . Besides, these diseases can manifest as acute or chronic problems and can be incapacitating for their patients leading to huge costs for health systems particularly for chronic. pain. The causes of MSDs can be exposure to work-related or ergonomic risk factors and individual related risk factors. Repeated manual labor, lifting heavy loads, prolonged static work, overexertion, vibration, or working in an awkward posture usually leads work related MSDs. Extended working hours and uncomfortable postures were significantly associated with the risk of MSDs and workers who work for conventional working hours (8 hrs per day) were less prone to develop MSDs. Among Ready Made Garments workers lower back and upper back are the most affected area due to prolonged work and wrong posture. Moreover, work breaks, working under pressure or with deadlines, poor job design, job insecurity, and lack of social support from colleagues and supervisors are directly related to stress, and that stress can appear in increased muscle tension and other stress-related differences to the body, making workers more vulnerable to developing MSDs. Workers often work for extended hours in awkward position can also suffer MSDs. Age, gender, health and lifestyle are the individual risk factors that are responsible for the higher risk of MSDs and other chronic conditions . Person's skills and functions are affected by Musculoskeletal disorders and therefore influence their activities of daily life . Back and neck pain, osteoarthritis , rheumatoid arthritis and fractures are the most disabling conditions. Moreover, these are often correlated with major non-communicable co-morbidities (ischemic heart disease, stroke, cancer and chronic respiratory disease) and they jointly increase disabilities and deaths. The most prevalent MSDs in Bangladesh is low back pain (18.6%). Rapid urbanization, transition to sedentary work, weight gain; domestic and professional activities in banding posture may be responsible for the higher prevalence of low back pain in Bangladesh. The second commonest MSDs are knee osteoarthritis (7.3%) and it is related to more knee usage during occupational and household chores in Bangladesh. Besides these soft tissue injuries and rheumatism can be the third commonest disorders (3.8%) Among the female readymade garment workers in Bangladesh, the prevalence of lower back pain (41%) was the most leading accompanied by pain in the knees(33%) and neck pain (28%). Musculoskeletal disorders are mostly preventable and prevention is the best treatment. Therefore, understanding what these disorders are and the risk factors that contribute to their development is very fundamental. Furthermore, developing an effective and efficient prevention strategy requires, risk assessment process and implementation of technical, organizational, and person-oriented measures. The causes of MSDs can be exposure to work-related or ergonomic risk factors and individual related risk factors. Repeated manual labor, lifting heavy loads, prolonged static work, overexertion, vibration, or working in an awkward posture usually leads work related MSDs. Extended working hours and uncomfortable postures were significantly associated with the risk of MSDs and workers who work for conventional working hours (8 hrs per day) were less prone to develop MSDs. Among Ready Made Garments workers lower back and upper back are the most affected area due to prolonged work and wrong posture. Moreover, work breaks, working under pressure or with deadlines, poor job design, job insecurity, and lack of social support from colleagues and supervisors are directly related to stress, and that stress can appear in increased muscle tension and other stress-related differences to the body, making workers more vulnerable to developing MSDs. Workers often work for extended hours in awkward position can also suffer MSDs. Age, gender, health and lifestyle are the individual risk factors that are responsible for the higher risk of MSDs and other chronic conditions .Person's skills and functions are affected by Musculoskeletal disorders and therefore influence their activities of daily life . Back and neck pain, osteoarthritis , rheumatoid arthritis and fractures are the most disabling conditions. Moreover, these are often correlated with major non-communicable co-morbidities (ischemic heart disease, stroke, cancer and chronic respiratory disease) and they jointly increase disabilities and deaths. The most prevalent MSDs in Bangladesh is low back pain (18.6%). Rapid urbanization, transition to sedentary work, weight gain; domestic and professional activities in banding posture may be responsible for the higher prevalence of low back pain in Bangladesh. The second commonest MSDs are knee osteoarthritis (7.3%) and it is related to more knee usage during occupational and household chores in Bangladesh. Besides these soft tissue injuries and rheumatism can be the third commonest disorders (3.8%) Among the female readymade garment workers in Bangladesh, the prevalence of lower back pain (41%) was the most leading accompanied by pain in the knees(33%) and neck pain (28%). Musculoskeletal disorders are mostly preventable and prevention is the best treatment. Therefore, understanding what these disorders are and the risk factors that contribute to their development is very fundamental. Furthermore, developing an effective and efficient prevention strategy requires, risk assessment process and implementation of technical, organizational, and person-oriented measures. According to WHO, "mental health is a state of well-being in which the individual realizes his or her own abilities, can cope with the normal stresses of life, can work productively and fruitfully, and is able to make a contribution to his or her community." The most difficult problem to tackle in this country is perhaps the environmental sanitation problem which is multi-faceted and multi-factorial. The twin problems of environmental sanitation are lack of safe drinking water in many areas of the country and preventive methods of excreta disposal. [ citation needed ]Bangladesh suffers from some of the most severe malnutrition problems. The present per capita intake is only 1850 kilocalorie which is by any standard, much below the required need. Malnutrition results from the convergence of poverty, inequitable food distribution, disease, illiteracy, rapid population growth and environmental risks, compounded by cultural and social inequities. Severe undernutrition exists mainly among families of landless agricultural labourers and farmers with a smallholding . [ citation needed ] Specific nutritional problems in the country are: [ citation needed ] Child malnutrition in Bangladesh is amongst the highest in the world. Two-thirds of the children under the age of five are under-nourished and about 60% of children under age six, are stunted. As of 1985, more than 45 percent of rural families and 76 percent of urban families were below the acceptable caloric intake level. Malnutrition is passed on through generations as malnourished mothers give birth to malnourished children. About one-third of babies in Bangladesh are born with low birth weight, increasing infant mortality rate, and an increased risk of diabetes and heart ailments in adulthood. One neonate dies in Bangladesh every three to four minutes; 120 000 neonates die every year. The World Bank estimates that Bangladesh is ranked 1st in the world of the number of children suffering from malnutrition. In Bangladesh, 26% of the population are undernourished and 46% of the children suffers from moderate to severe underweight problem. 43% of children under 5 years old are stunted. One in five preschool age children are vitamin A deficient and one in two are anaemic. Women also suffer most from malnutrition. To provide their family with food they pass on quality food which are essential for their nutrition. Most terrain of Bangladesh is low-lying and is prone to flooding. A large population of the country lives in areas that are at risk of experiencing extreme annual flooding that brings large destruction to the crops. Every year, 20% to 30% of Bangladesh is flooded. Floods threaten food security and their effects on agricultural production cause food shortage. The health and sanitation environment also affects malnutrition. Inadequacies in water supply, hygiene and sanitation have direct impacts on infectious diseases, such as malaria, parasitic diseases, and schistosomiasis . People are exposed to both water scarcity and poor water quality. Groundwater is often found to contain high arsenic concentration. Sanitation coverage in rural areas was only 35% in 1995. Almost one in three people in Bangladesh defecates in the open among the poorest families. Only 32% of the latrines in rural areas attain the international standards for a sanitary latrine. People are exposed to feces in their environment daily. The immune system falls and the disease processes exacerbate loss of nutrients, which worsens malnutrition. The diseases also contribute through the loss of appetite, lowered absorption of vitamins and nutrients, and loss of nutrients through diarrhoea or vomiting. Unemployment and job problems also lead to malnutrition in Bangladesh. In 2010, the unemployment rate was 5.1%. [ unreliable source? ] People do not have working facilities all year round and they are unable to afford the minimum cost of a nutritious diet due to the unsteady income. Undernourished mothers often give birth to infants who will have difficulty with development, pertaining to health problems such as wasting, stunting, underweight, anaemia, night blindness and iodine deficiency. As a result, Bangladesh has a high child mortality rate and is ranked 57 in the under-5 mortality rank. As 40% of the population in Bangladesh are children, malnutrition and its health effects among children can potentially lead to a lower educational attainment rate. Only 50% of an age group of children in Bangladesh managed to enroll into secondary school education. This would result in a low-skilled and low productivity workforce which would affect the economic growth rate of Bangladesh with only 3% GDP growth in 2009. Many programmes and efforts have been implemented to solve the problem of malnutrition in Bangladesh. UNICEF together with the government of Bangladesh and many other NGOs such as Helen Keller International , focus on improving the nutritional access of the population throughout their life-cycle from infants to the child-bearing mother. The impacts of the intervention are significant. Night blindness has reduced from 3.76% to 0.04% and iodine deficiency among school-aged children has decreased from 42.5% to 33.8%. Most terrain of Bangladesh is low-lying and is prone to flooding. A large population of the country lives in areas that are at risk of experiencing extreme annual flooding that brings large destruction to the crops. Every year, 20% to 30% of Bangladesh is flooded. Floods threaten food security and their effects on agricultural production cause food shortage. The health and sanitation environment also affects malnutrition. Inadequacies in water supply, hygiene and sanitation have direct impacts on infectious diseases, such as malaria, parasitic diseases, and schistosomiasis . People are exposed to both water scarcity and poor water quality. Groundwater is often found to contain high arsenic concentration. Sanitation coverage in rural areas was only 35% in 1995. Almost one in three people in Bangladesh defecates in the open among the poorest families. Only 32% of the latrines in rural areas attain the international standards for a sanitary latrine. People are exposed to feces in their environment daily. The immune system falls and the disease processes exacerbate loss of nutrients, which worsens malnutrition. The diseases also contribute through the loss of appetite, lowered absorption of vitamins and nutrients, and loss of nutrients through diarrhoea or vomiting. Unemployment and job problems also lead to malnutrition in Bangladesh. In 2010, the unemployment rate was 5.1%. [ unreliable source? ] People do not have working facilities all year round and they are unable to afford the minimum cost of a nutritious diet due to the unsteady income. Undernourished mothers often give birth to infants who will have difficulty with development, pertaining to health problems such as wasting, stunting, underweight, anaemia, night blindness and iodine deficiency. As a result, Bangladesh has a high child mortality rate and is ranked 57 in the under-5 mortality rank. As 40% of the population in Bangladesh are children, malnutrition and its health effects among children can potentially lead to a lower educational attainment rate. Only 50% of an age group of children in Bangladesh managed to enroll into secondary school education. This would result in a low-skilled and low productivity workforce which would affect the economic growth rate of Bangladesh with only 3% GDP growth in 2009. Many programmes and efforts have been implemented to solve the problem of malnutrition in Bangladesh. UNICEF together with the government of Bangladesh and many other NGOs such as Helen Keller International , focus on improving the nutritional access of the population throughout their life-cycle from infants to the child-bearing mother. The impacts of the intervention are significant. Night blindness has reduced from 3.76% to 0.04% and iodine deficiency among school-aged children has decreased from 42.5% to 33.8%. Maternal and child health is an important issue in a country like Bangladesh . Bangladesh is one of the developing countries who signed onto achieving the Sustainable Development Goals (SDGs). In the new target of SDGs the issue of maternal and child health is fitting under goal number three. Over the last two decades, national health policy and strategies progressed with significant achievements. Still now Bangladesh is aiming to reduce maternal and child mortality through its renovation process. The MDG Goal five target was to reduce the maternal mortality rate (MMR) from 574 to 143 deaths per 100,000 live births by 2015 in Bangladesh. There has been a significant downfall in the MMR rates; however, the trajectory is not enough to meet the targets. The maternal mortality rate (MMR) per 100,000 live births was estimated at 385 globally and 563 in Bangladesh in 1990. In 2015, MMR was 176 per 100,00 live births in Bangladesh and 216 globally. However, the number of deaths of women while pregnant or within 42 days of termination of the pregnancy in Bangladesh were 21,000 in 1990 which reduced dramatically and reached at 5,500 in 2015. The reduction in maternal mortality is attributed to multiple factors. The factors like improved assess and utilization of health facilities, improvements in female education and per capita income helped to achieve the goal. Fertility reduction have also contributed to reduce MMR by lowering the number of high risk, high parity births. However, the antenatal care (ANC) coverage has been increased between 1990 and 2014. The proportion of women receiving at least one antenatal visit rose from 28% in 1990 to 64% in 2014 from a medically trained provider. In 2014, the population of women aged 15–49 who received postnatal care within 2 days after giving birth was 36%, antenatal coverage for at least four visits was 31%, proportion of births attended by skilled health personnel was 42%, caesarean section was 23%, proportion of women age 20–24 years old who gave birth before 18 years was 36%, number of women age 15–49 years with a live birth delivery in a health facility was 37% and births who had their first postnatal check-up within the first two days after birth was 31% in Bangladesh. The major causes of Maternal Mortality are - postpartum haemorrhage (31%), Eclampsia /pre-eclampsia (20%), delayed & obstructed labour (7%), Abortion (1%), other direct cause (5%) and indirect cause (35%). In Bangladesh prevalence of undernourishment among adolescent girls and pregnant women is very high, and one-third of such women have low BMI and anemia . In urban area, anemia and Vitamin A deficiency was found to be prevalent among most of the pregnant mothers. To achieve the MDG-4 target, Bangladesh has experienced a significant reduction of child mortality over the past decades. But under 5 mortality must be reduced to achieve the SDG Goal three target. Neonatal mortality is a puissant part of overall child mortality. Neonatal mortality rate of Bangladesh fell gradually from 1990 to 2015. In 1990, per 1000 live births under five mortality rate and infant mortality rate was 93 and 64 globally but in Bangladesh it was higher than the global average. In 2017, global under five mortality rate and infant mortality rate was 39 and 29 per 1000 live births respectively and in Bangladesh this rate was lower than the world average. In 1990, the number of under-5 deaths, infant deaths, and neonatal deaths were 532193.00, 368085.00 and 240316.00 and in 2017 the number reduced and reached at 99608.00, 82240.00 and 56341.00 respectively. The major causes of under-5 child mortality were preterm birth 18%, intrapartum 13.8%, pneumonia 13.5%, sepsis 11%, congenital 9.1%, injury 7.9%, diarrhoea 7.1%, measles 1.9% and other 15.9%. A study on risk factors of infant mortality, using data from the 2014 Bangladesh Demographic and Health Survey, showed that the risk of mortality in Bangladesh is 1.5 times higher for smaller babies. Infant mortality in Bangladesh is also lower for the urban population as well as for higher economic classes (which have greater access to health services). In Bangladesh, just over half of all children were anemic in 2011. A number of interventions have taken to address this issue, including the distribution of iron supplements and deworming tablets every 6 months till 5 years of age. However, children age 6–59 months receive Vitamin-A capsules twice a year. Between 2004 and 2014 the prevalence of children who are stunted, and underweight declined 29% and 23% respectively. But the prevalence of wasting showed very little change during this period. In the health system of Bangladesh, maternal and Child Health (MCH) services have been given highest priority. At the society level, MCH services are provided by the Family Welfare Assistants and Health Assistants . A Family Welfare Visitor (FWV) along with a Sub‑Assistant Community Medical Officer or Medical Assistants are responsible for providing the services, at the union level. At Upazila level, Medical officer provides MCH services in Upazila Health Complex. The activities of the Maternal and Child Health unit along with other maternal health care services are overseen by Upazila Health and Family Planning Officer in the Upazila Health Complex. The district hospitals provide maternal services through an outpatient consultation center and a labor ward. However, to provide MCH services private sector is playing supplementary and often competitive role in health sector with public one. NGOs also have a significant role providing primary, reproductive and family planning services. Union Ward Union Health and Family Welfare Centres Community Clinic In following decades, Bangladesh government's policy concentrated on reduction of population growth ; policy perceived that a consistent maternal and child health based family planning programme would help to achieve development goals. The Health and Population Sector Strategy (HPSS) was developed in 1997. The following seven strategies were included in the HPSP (MOHFW, 1998): 1) Focus on Emergency Obstetric Care for reducing maternal mortality, 2) Provision of Essential Obstetric Care/Basic maternity care services for promotion of "good practices" including early detection and appropriate referral of complications 3) Addressing the needs of women through a woman friendly hospital initiative 4) Communication for behaver change and development 5) Involvement of professional bodies 6) Stakeholder participation 7) Promotion of innovation. This policy document is theoretical framework of what is necessary and expected for improvement of maternal health situation in national level and It includes maternal services such as emergency obstetric care, antenatal care, skilled attendance, postnatal care, neonatal care and family planning. The MDG Goal five target was to reduce the maternal mortality rate (MMR) from 574 to 143 deaths per 100,000 live births by 2015 in Bangladesh. There has been a significant downfall in the MMR rates; however, the trajectory is not enough to meet the targets. The maternal mortality rate (MMR) per 100,000 live births was estimated at 385 globally and 563 in Bangladesh in 1990. In 2015, MMR was 176 per 100,00 live births in Bangladesh and 216 globally. However, the number of deaths of women while pregnant or within 42 days of termination of the pregnancy in Bangladesh were 21,000 in 1990 which reduced dramatically and reached at 5,500 in 2015. The reduction in maternal mortality is attributed to multiple factors. The factors like improved assess and utilization of health facilities, improvements in female education and per capita income helped to achieve the goal. Fertility reduction have also contributed to reduce MMR by lowering the number of high risk, high parity births. However, the antenatal care (ANC) coverage has been increased between 1990 and 2014. The proportion of women receiving at least one antenatal visit rose from 28% in 1990 to 64% in 2014 from a medically trained provider. In 2014, the population of women aged 15–49 who received postnatal care within 2 days after giving birth was 36%, antenatal coverage for at least four visits was 31%, proportion of births attended by skilled health personnel was 42%, caesarean section was 23%, proportion of women age 20–24 years old who gave birth before 18 years was 36%, number of women age 15–49 years with a live birth delivery in a health facility was 37% and births who had their first postnatal check-up within the first two days after birth was 31% in Bangladesh. The major causes of Maternal Mortality are - postpartum haemorrhage (31%), Eclampsia /pre-eclampsia (20%), delayed & obstructed labour (7%), Abortion (1%), other direct cause (5%) and indirect cause (35%). In Bangladesh prevalence of undernourishment among adolescent girls and pregnant women is very high, and one-third of such women have low BMI and anemia . In urban area, anemia and Vitamin A deficiency was found to be prevalent among most of the pregnant mothers. To achieve the MDG-4 target, Bangladesh has experienced a significant reduction of child mortality over the past decades. But under 5 mortality must be reduced to achieve the SDG Goal three target. Neonatal mortality is a puissant part of overall child mortality. Neonatal mortality rate of Bangladesh fell gradually from 1990 to 2015. In 1990, per 1000 live births under five mortality rate and infant mortality rate was 93 and 64 globally but in Bangladesh it was higher than the global average. In 2017, global under five mortality rate and infant mortality rate was 39 and 29 per 1000 live births respectively and in Bangladesh this rate was lower than the world average. In 1990, the number of under-5 deaths, infant deaths, and neonatal deaths were 532193.00, 368085.00 and 240316.00 and in 2017 the number reduced and reached at 99608.00, 82240.00 and 56341.00 respectively. The major causes of under-5 child mortality were preterm birth 18%, intrapartum 13.8%, pneumonia 13.5%, sepsis 11%, congenital 9.1%, injury 7.9%, diarrhoea 7.1%, measles 1.9% and other 15.9%. A study on risk factors of infant mortality, using data from the 2014 Bangladesh Demographic and Health Survey, showed that the risk of mortality in Bangladesh is 1.5 times higher for smaller babies. Infant mortality in Bangladesh is also lower for the urban population as well as for higher economic classes (which have greater access to health services). In Bangladesh, just over half of all children were anemic in 2011. A number of interventions have taken to address this issue, including the distribution of iron supplements and deworming tablets every 6 months till 5 years of age. However, children age 6–59 months receive Vitamin-A capsules twice a year. Between 2004 and 2014 the prevalence of children who are stunted, and underweight declined 29% and 23% respectively. But the prevalence of wasting showed very little change during this period. In the health system of Bangladesh, maternal and Child Health (MCH) services have been given highest priority. At the society level, MCH services are provided by the Family Welfare Assistants and Health Assistants . A Family Welfare Visitor (FWV) along with a Sub‑Assistant Community Medical Officer or Medical Assistants are responsible for providing the services, at the union level. At Upazila level, Medical officer provides MCH services in Upazila Health Complex. The activities of the Maternal and Child Health unit along with other maternal health care services are overseen by Upazila Health and Family Planning Officer in the Upazila Health Complex. The district hospitals provide maternal services through an outpatient consultation center and a labor ward. However, to provide MCH services private sector is playing supplementary and often competitive role in health sector with public one. NGOs also have a significant role providing primary, reproductive and family planning services. Union Ward Union Health and Family Welfare Centres Community ClinicIn following decades, Bangladesh government's policy concentrated on reduction of population growth ; policy perceived that a consistent maternal and child health based family planning programme would help to achieve development goals. The Health and Population Sector Strategy (HPSS) was developed in 1997. The following seven strategies were included in the HPSP (MOHFW, 1998): 1) Focus on Emergency Obstetric Care for reducing maternal mortality, 2) Provision of Essential Obstetric Care/Basic maternity care services for promotion of "good practices" including early detection and appropriate referral of complications 3) Addressing the needs of women through a woman friendly hospital initiative 4) Communication for behaver change and development 5) Involvement of professional bodies 6) Stakeholder participation 7) Promotion of innovation. This policy document is theoretical framework of what is necessary and expected for improvement of maternal health situation in national level and It includes maternal services such as emergency obstetric care, antenatal care, skilled attendance, postnatal care, neonatal care and family planning. Occupational health deals with all aspects of health and safety in the workplace and has a strong focus on primary prevention of hazards . Bangladesh has emerged as a key player in RMG ( Ready Made Garment ) sector since 1978. Textiles and clothing account for about 85% of total export earnings of Bangladesh. Before the starting of RMG sector, woman's participation in the formal economy has been low compared to man but in late 1980s after orienting this sector, the scenario has dramatically changed and now 80 percent of the total employment in RMG sector is occupied by female worker. But the health of this 'women-driven sector' is neglected. Bangladesh has made significant progress in reducing maternal mortality . However, the work environment of RMG has the potential to create health problems, particularly for vulnerable groups such as pregnant women. This paper explores perceptions of health problems during pregnancy of factory workers, in this important industry in Bangladesh. Female workers reported that participation in paid work created an opportunity for them to earn money but pregnancy and the nature of the job, including being pressured to meet the production quota , pressure to leave the job because of their pregnancy and withholding of maternity benefits, cause stress, anxiety and may contribute to hypertensive disorders of pregnancy . This was confirmed by factory doctors who suggested that developing hypertensive disorders during pregnancy was influenced by the nature of work and stress . The employers seemed focused on profit and meeting quotas and the health of pregnant workers appeared to be a lower priority. The women reported that they do not visit the factory doctor for an ante-natal check-up when they first suspect that they are pregnant because they feel they need to hide their pregnancy from their supervisors. For example, they needs to meet a production quota of one hundred pieces per hour. If they lag behind the quota due to their pregnancy, their supervisors will encourage them to leave the job. They will also not be assigned to do overtime to earn extra money. They only go to the factory clinic for a check-up during pregnancy when their pregnancy becomes visible. They also do not go to the private clinics because of the cost. Doctor's room: Sickness Analysis Medical Issue Register Treatment Register Medicine Stock Register First Aid Training register Accident / injury Register Maternity Follow up file Medical Consolation Graph Maintain first aid kit Bangladesh has emerged as a key player in RMG ( Ready Made Garment ) sector since 1978. Textiles and clothing account for about 85% of total export earnings of Bangladesh. Before the starting of RMG sector, woman's participation in the formal economy has been low compared to man but in late 1980s after orienting this sector, the scenario has dramatically changed and now 80 percent of the total employment in RMG sector is occupied by female worker. But the health of this 'women-driven sector' is neglected.Bangladesh has made significant progress in reducing maternal mortality . However, the work environment of RMG has the potential to create health problems, particularly for vulnerable groups such as pregnant women. This paper explores perceptions of health problems during pregnancy of factory workers, in this important industry in Bangladesh. Female workers reported that participation in paid work created an opportunity for them to earn money but pregnancy and the nature of the job, including being pressured to meet the production quota , pressure to leave the job because of their pregnancy and withholding of maternity benefits, cause stress, anxiety and may contribute to hypertensive disorders of pregnancy . This was confirmed by factory doctors who suggested that developing hypertensive disorders during pregnancy was influenced by the nature of work and stress . The employers seemed focused on profit and meeting quotas and the health of pregnant workers appeared to be a lower priority. The women reported that they do not visit the factory doctor for an ante-natal check-up when they first suspect that they are pregnant because they feel they need to hide their pregnancy from their supervisors. For example, they needs to meet a production quota of one hundred pieces per hour. If they lag behind the quota due to their pregnancy, their supervisors will encourage them to leave the job. They will also not be assigned to do overtime to earn extra money. They only go to the factory clinic for a check-up during pregnancy when their pregnancy becomes visible. They also do not go to the private clinics because of the cost. Doctor's room: Sickness Analysis Medical Issue Register Treatment Register Medicine Stock Register First Aid Training register Accident / injury Register Maternity Follow up file Medical Consolation Graph Maintain first aid kit The use of illegal drugs or the use of prescription or over-the-counter drugs or alcohol for purposes other than those for which they are meant to be used, or in excessive amounts. Different types of social, physical, emotional, and job-related problems can arise from substance abuse. This has become a matter of headache in recent years with overuse of substances like tobacco, alcohol, yaba along with some other prescribed drugs like sedatives or drugs used for anxiety disorders. Risk factors can influence drug abuse in several ways. The more risks a child is exposed to, the more likely the child will abuse drugs. Some risk factors may be more powerful than others at certain stages in development, such as peer pressure during the teenage years; just as some protective factors, such as a strong parent-child bond, can have a greater impact on reducing risks during the early years. An important goal of prevention is to change the balance between risk and protective factors so that protective factors outweigh risk factors. Table 1- Risk Factors and Protective Factors of Substance Abuse. Table 2- Prevalence of Alcohol and Drug use disorders. Approximately 126,000 deaths accounting for 13.5% of deaths were caused by tobacco from any cause in Bangladesh in 2018. Nearly 1.5 million adults were suffering from diseases attributable to tobacco use and due to exposure to secondhand smoke around 61,000 children were suffering from diseases. The direct healthcare costs attributable to tobacco use amounted to BDT 83.9 billion annually and the annual productivity loss, due to morbidity and premature mortality from tobacco-related diseases, was estimated to be BDT 221.7 billion. Thus, the total annual economic cost amounted to BDT 305.6 billion ($3.61 billion) which is equivalent to 1.4% of the GDP of Bangladesh in 2017–18. Smoking increases the risk of cancer, heart disease, stroke, lung diseases, diabetes, chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, tuberculosis, certain eye diseases and problems of the immune system, including rheumatoid arthritis. In Bangladesh, an alcoholic beverage is defined as any liquor with an alcohol content of ≥0.5%. These alcoholic beverages include beer (5% alcohol in volume), wine (12% alcohol in volume), spirits (40% alcohol in volume) and locally made alcoholic beverages (variable alcohol content). Locally produced alcoholic beverages are made from sorghum, maize, millet, rice, cider, fruit wine or fortified wine ( tari , bangle mod , haria , choani , do chuani , mohua , etc.). Though alcohol use is low in Bangladesh, those who use alcohol frequently binge drink, which is a public health concern. The use is prevalent among men, younger age groups, labourers, salaried government and nongovernment employees and businessmen, current smokers and those with a minimal educational background. Harmful use of alcohol is increasingly becoming a national concern as very few people with alcohol problems seek de-addiction treatment in Bangladesh. Injuries including motor vehicle crashes, falls, drownings, and burns Violence (homicide, suicide, sexual assault, and intimate partner violence) Alcohol poisoning Risky sexual behaviors such as unprotected sex or sex with multiple partners which may result in unintended pregnancy or sexually transmitted diseases Miscarriage and stillbirth or fetal abnormality. High blood pressure, heart disease, stroke, liver disease Learning and memory problem along with social problems Alcohol dependence etc. The main groups of illicit drugs used in international statistics are opioids, cocaine, amphetamines and cannabis. However, there is a range of other illicit drugs included in international drug control treaties. Deaths from drug use are of two types: – direct deaths which result from illicit drug overdoses. – indirect deaths resulting from illicit drug use acting as a risk factor for the development of various diseases and injury. Table 3- Deaths due to Illicit Drug Abuse. Death Weakened immune system, increasing the risk of illness and infection Heart conditions ranging from abnormal heart rates to heart attacks and collapsed veins and blood vessel infections from injected drugs Nausea, abdominal pain, changes in appetite and weight loss Liver damage or liver failure Seizures, stroke, mental confusion and brain damage Lung disease Problems with memory, attention and decision-making Behavioral problems including paranoia, aggressiveness, hallucination, addiction, impulsiveness, loss of self-control etc. Previously Bangladesh had no adequate and enabling law to handle the condition created by drug abuse and the related issues.The Government of the People's Republic of Bangladesh enacted the Narcotics Control Act in 1990 annulling all the colonial laws with a view to encountering drug problem true to the aspiration of the society. Risk factors can influence drug abuse in several ways. The more risks a child is exposed to, the more likely the child will abuse drugs. Some risk factors may be more powerful than others at certain stages in development, such as peer pressure during the teenage years; just as some protective factors, such as a strong parent-child bond, can have a greater impact on reducing risks during the early years. An important goal of prevention is to change the balance between risk and protective factors so that protective factors outweigh risk factors. Table 1- Risk Factors and Protective Factors of Substance Abuse. Table 2- Prevalence of Alcohol and Drug use disorders. Approximately 126,000 deaths accounting for 13.5% of deaths were caused by tobacco from any cause in Bangladesh in 2018. Nearly 1.5 million adults were suffering from diseases attributable to tobacco use and due to exposure to secondhand smoke around 61,000 children were suffering from diseases. The direct healthcare costs attributable to tobacco use amounted to BDT 83.9 billion annually and the annual productivity loss, due to morbidity and premature mortality from tobacco-related diseases, was estimated to be BDT 221.7 billion. Thus, the total annual economic cost amounted to BDT 305.6 billion ($3.61 billion) which is equivalent to 1.4% of the GDP of Bangladesh in 2017–18. Smoking increases the risk of cancer, heart disease, stroke, lung diseases, diabetes, chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, tuberculosis, certain eye diseases and problems of the immune system, including rheumatoid arthritis. Smoking increases the risk of cancer, heart disease, stroke, lung diseases, diabetes, chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, tuberculosis, certain eye diseases and problems of the immune system, including rheumatoid arthritis. In Bangladesh, an alcoholic beverage is defined as any liquor with an alcohol content of ≥0.5%. These alcoholic beverages include beer (5% alcohol in volume), wine (12% alcohol in volume), spirits (40% alcohol in volume) and locally made alcoholic beverages (variable alcohol content). Locally produced alcoholic beverages are made from sorghum, maize, millet, rice, cider, fruit wine or fortified wine ( tari , bangle mod , haria , choani , do chuani , mohua , etc.). Though alcohol use is low in Bangladesh, those who use alcohol frequently binge drink, which is a public health concern. The use is prevalent among men, younger age groups, labourers, salaried government and nongovernment employees and businessmen, current smokers and those with a minimal educational background. Harmful use of alcohol is increasingly becoming a national concern as very few people with alcohol problems seek de-addiction treatment in Bangladesh. Injuries including motor vehicle crashes, falls, drownings, and burns Violence (homicide, suicide, sexual assault, and intimate partner violence) Alcohol poisoning Risky sexual behaviors such as unprotected sex or sex with multiple partners which may result in unintended pregnancy or sexually transmitted diseases Miscarriage and stillbirth or fetal abnormality. High blood pressure, heart disease, stroke, liver disease Learning and memory problem along with social problems Alcohol dependence etc. Injuries including motor vehicle crashes, falls, drownings, and burns Violence (homicide, suicide, sexual assault, and intimate partner violence) Alcohol poisoning Risky sexual behaviors such as unprotected sex or sex with multiple partners which may result in unintended pregnancy or sexually transmitted diseases Miscarriage and stillbirth or fetal abnormality. High blood pressure, heart disease, stroke, liver disease Learning and memory problem along with social problems Alcohol dependence etc. The main groups of illicit drugs used in international statistics are opioids, cocaine, amphetamines and cannabis. However, there is a range of other illicit drugs included in international drug control treaties. Deaths from drug use are of two types: – direct deaths which result from illicit drug overdoses. – indirect deaths resulting from illicit drug use acting as a risk factor for the development of various diseases and injury. Table 3- Deaths due to Illicit Drug Abuse. Death Weakened immune system, increasing the risk of illness and infection Heart conditions ranging from abnormal heart rates to heart attacks and collapsed veins and blood vessel infections from injected drugs Nausea, abdominal pain, changes in appetite and weight loss Liver damage or liver failure Seizures, stroke, mental confusion and brain damage Lung disease Problems with memory, attention and decision-making Behavioral problems including paranoia, aggressiveness, hallucination, addiction, impulsiveness, loss of self-control etc. Previously Bangladesh had no adequate and enabling law to handle the condition created by drug abuse and the related issues.The Government of the People's Republic of Bangladesh enacted the Narcotics Control Act in 1990 annulling all the colonial laws with a view to encountering drug problem true to the aspiration of the society. Death Weakened immune system, increasing the risk of illness and infection Heart conditions ranging from abnormal heart rates to heart attacks and collapsed veins and blood vessel infections from injected drugs Nausea, abdominal pain, changes in appetite and weight loss Liver damage or liver failure Seizures, stroke, mental confusion and brain damage Lung disease Problems with memory, attention and decision-making Behavioral problems including paranoia, aggressiveness, hallucination, addiction, impulsiveness, loss of self-control etc. Previously Bangladesh had no adequate and enabling law to handle the condition created by drug abuse and the related issues.The Government of the People's Republic of Bangladesh enacted the Narcotics Control Act in 1990 annulling all the colonial laws with a view to encountering drug problem true to the aspiration of the society. There is a huge burden of the neglected tropical diseases (NTDs) in Bangladesh, particularly for Kala-azar ; Lymphatic Filariasis , Dengue and Chikungunya . On a global scale, Bangladesh has a higher overall prevalence of NTDs compared to other low and middle income countries like Sri Lanka , Haiti , China due to its larger population, tropical climate and socio economic factors. Chikungunya is one of the neglected tropical diseases of Bangladesh. It is a viral disease which is transmitted to humans by infected mosquitoes – including Aedes aegypti and Aedes albopictus , which is present in Bangladesh. It is an RNA virus that belongs to the alphavirus genus of the family Togaviridae . It was first described during an outbreak in southern Tanzania in 1952. Since then, CHIKV has been reported to cause several large-scale outbreaks in Africa, India, Southeast Asia, Western Pacific and Americas. In the South-East Asia region, Chikungunya virus is maintained in the human population by a human-mosquito-human transmission cycle that differs from the sylvatic transmission cycle on the African continent. Chikungunya is a vector-borne disease transmitted to humans by the bites of infected female mosquitoes which breed in clean water collections in containers, tanks, disposables, junk material in domestic and peri-domestic situations besides natural habitats like tree holes, plantations etc. These mosquitoes can be found biting throughout daylight hours, though there may be peaks of activity in the early morning and late afternoon. A high vector density is seen in the post monsoon season that enhances the transmission. It causes fever and severe joint pain . Other symptoms include muscle pain , headache, nausea , fatigue and rash . Joint pain is often debilitating and can vary in duration. Chikungunya is rarely fatal. Symptoms are generally self-limiting and last for 2–3 days. The disease shares some clinical signs with dengue and zika , and can be misdiagnosed in areas where they are common. Here is the Clinical features of Chikungunya virus infections compared with dengue virus infections. Several methods can be used for diagnosis. Serological tests, such as enzyme-linked immunosorbent assays ( ELISA ), may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibody levels are highest 3 to 5 weeks after the onset of illness and persist for about 2 months. Samples collected during the first week after the onset of symptoms should be tested by both serological and virological methods ( RT-PCR ). There is no vaccine to prevent or anti-viral drugs to treat Chikungunya virus. Treatment is directed primarily at relieving the symptoms, including the joint pain using anti-pyretics , optimal analgesics and fluids. In Bangladesh, the first recognized outbreak of Chikungunya was reported in 2008 in two villages in the northwest part of the country adjacent to Indian border. Two small-scale outbreaks were documented in rural communities in 2011 and 2012. A massive outbreak of Chikungunya occurred in Bangladesh during the period of April–September 2017 and over two million people at Dhaka, the capital of Bangladesh were at risk of getting infected by the virus. A recent research study (1326 cases) was conducted (between 24 July and 5 August 2017) to investigate the clinical profiles, economic burden, and quality of life of Chikungunya affected individuals. Severe arthropathy is the most consistent clinical feature of chikungunya infection. In this study, all patients experienced Arthalgia (100%); Pain before fever (74.66%); Skin Rash(69.6%); Itching (60.9%); Headache (77.3%) and Myalgia (69.3%) (Figure-2). Also,t he severity of certain clinical manifestations of Chikungunya might depend on several factors including age, gender, immune status, genetic predisposition and co-morbid conditions. Children (<15 years) tended to have a higher proportion of oligo-arthralgia and skin rash; while morning stiffness , severity, and duration of pain were proportionally lower among children as compared to other age groups. Joint swelling was most commonly noted in elderly patients (60+ years), while the severity of pain was highest among adults (30–59 years). Chikungunya infection caused significant loss of productivity due to absenteeism from job. Prevention is entirely dependent upon taking steps to avoid mosquito bites and elimination of mosquito breeding sites. Wear full sleeve clothes and long dresses to cover the limbs. Use mosquito coils, repellents and electric vapour mats during the daytime. Use mosquito nets – to protect babies, old people and others, who may rest during the day. The effectiveness of such nets can be improved by treating them with permethrin (pyrethroid insecticide). Mosquitoes become infected when they bite people who are sick with Chikungunya. Mosquito nets and mosquito coils will effectively prevent mosquitoes from biting sick people. The Aedes mosquitoes that transmit Chikungunya breed in a wide variety of man-made containers which are common around human dwellings. These containers collect rainwater, and include discarded tires, flowerpots, old oil drums, animal water troughs, water storage vessels, and plastic food containers. These breeding sites can be eliminated by Draining water from coolers, tanks, barrels, drums and buckets, etc. Emptying coolers when not in use. Removing from the house all objects, e.g. plant saucers, etc. which have water collected in them. Chikungunya epidemics, with the high attack rate of CHIKV , affect a large number of people in a short period of time associated with early rain fall (early monsoon ) and this is also consistently seen in Bangladesh outbreak 2017. Pain, the most frequent clinical manifestation of Chikungunya, is difficult to control, compromising the quality of life, intense psychosocial and economic repercussions, causing a serious public health problem that requires a targeted approach. General physicians, Infectious disease specialists, Rheumatologist and other specialist, nurses, pain specialists, physiotherapists, social workers, and healthcare managers are required to overcome these challenges so that an explosive increase in CHIKV cases can be mitigated. Bangladesh is battling its worst dengue outbreak on record. The health care system is straining because of high number of sick people and hospitals are facing a shortage of beds and staff to care for patients. Dengue was initially documented in 1960s, known as 'Dacca fever' at the time.Since 2010, incidences of dengue seem to align with the wet season spanning from May to September and high temperatures. The climate is increasingly becoming conducive to the spread of dengue due to heavy rainfall, waterlogging. floods, rising temperatures, and unexpected alterations in the country's seasons. Epidemiology of dengue in Bangladesh: Between January 1 and August 19, 2023, Bangladesh reported 97,476 cases of dengue, resulting in 466 deaths. This outbreak affected 37.6% women and 17.8% children under 18. The World Health Organization noted that dengue had spread to all 64 districts in Bangladesh. In Cox's Bazar, specific Rohingya camps were hotspots for dengue cases. It is estimated that around 80-90% people in Dhaka and Chittagong city had been infected with dengue in their lifetime. Causes of high dengue prevalence in Bangladesh: Rapidly growing and densely populated cities Unplanned urbanisation People store water in buckets, plastic containers and elsewhere because of water supply problem where mosquitoes can live all year round. Increasing number of high rise buildings with car parks in the basement where people wash their car, which is ideal for mosquitoes. Plenty of water lying around the construction sites. Aedes aegypti has developed resistance to insecticides like malathion. A cost-effective vaccine perhaps the best hope for Bangladesh. A promising single-dose vaccine developed by the US National Institutes of Health (Bethesda, MD, USA) in collaboration with the University of Vermont Vaccine Testing Center (Burlington, VT, USA) and Johns Hopkins University (Baltimore, MD, USA) is under clinical trial. Chikungunya is one of the neglected tropical diseases of Bangladesh. It is a viral disease which is transmitted to humans by infected mosquitoes – including Aedes aegypti and Aedes albopictus , which is present in Bangladesh. It is an RNA virus that belongs to the alphavirus genus of the family Togaviridae . It was first described during an outbreak in southern Tanzania in 1952. Since then, CHIKV has been reported to cause several large-scale outbreaks in Africa, India, Southeast Asia, Western Pacific and Americas. In the South-East Asia region, Chikungunya virus is maintained in the human population by a human-mosquito-human transmission cycle that differs from the sylvatic transmission cycle on the African continent. Chikungunya is a vector-borne disease transmitted to humans by the bites of infected female mosquitoes which breed in clean water collections in containers, tanks, disposables, junk material in domestic and peri-domestic situations besides natural habitats like tree holes, plantations etc. These mosquitoes can be found biting throughout daylight hours, though there may be peaks of activity in the early morning and late afternoon. A high vector density is seen in the post monsoon season that enhances the transmission. It causes fever and severe joint pain . Other symptoms include muscle pain , headache, nausea , fatigue and rash . Joint pain is often debilitating and can vary in duration. Chikungunya is rarely fatal. Symptoms are generally self-limiting and last for 2–3 days. The disease shares some clinical signs with dengue and zika , and can be misdiagnosed in areas where they are common. Here is the Clinical features of Chikungunya virus infections compared with dengue virus infections. Several methods can be used for diagnosis. Serological tests, such as enzyme-linked immunosorbent assays ( ELISA ), may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibody levels are highest 3 to 5 weeks after the onset of illness and persist for about 2 months. Samples collected during the first week after the onset of symptoms should be tested by both serological and virological methods ( RT-PCR ). There is no vaccine to prevent or anti-viral drugs to treat Chikungunya virus. Treatment is directed primarily at relieving the symptoms, including the joint pain using anti-pyretics , optimal analgesics and fluids. In Bangladesh, the first recognized outbreak of Chikungunya was reported in 2008 in two villages in the northwest part of the country adjacent to Indian border. Two small-scale outbreaks were documented in rural communities in 2011 and 2012. A massive outbreak of Chikungunya occurred in Bangladesh during the period of April–September 2017 and over two million people at Dhaka, the capital of Bangladesh were at risk of getting infected by the virus. A recent research study (1326 cases) was conducted (between 24 July and 5 August 2017) to investigate the clinical profiles, economic burden, and quality of life of Chikungunya affected individuals. Severe arthropathy is the most consistent clinical feature of chikungunya infection. In this study, all patients experienced Arthalgia (100%); Pain before fever (74.66%); Skin Rash(69.6%); Itching (60.9%); Headache (77.3%) and Myalgia (69.3%) (Figure-2). Also,t he severity of certain clinical manifestations of Chikungunya might depend on several factors including age, gender, immune status, genetic predisposition and co-morbid conditions. Children (<15 years) tended to have a higher proportion of oligo-arthralgia and skin rash; while morning stiffness , severity, and duration of pain were proportionally lower among children as compared to other age groups. Joint swelling was most commonly noted in elderly patients (60+ years), while the severity of pain was highest among adults (30–59 years). Chikungunya infection caused significant loss of productivity due to absenteeism from job. Prevention is entirely dependent upon taking steps to avoid mosquito bites and elimination of mosquito breeding sites. Wear full sleeve clothes and long dresses to cover the limbs. Use mosquito coils, repellents and electric vapour mats during the daytime. Use mosquito nets – to protect babies, old people and others, who may rest during the day. The effectiveness of such nets can be improved by treating them with permethrin (pyrethroid insecticide). Mosquitoes become infected when they bite people who are sick with Chikungunya. Mosquito nets and mosquito coils will effectively prevent mosquitoes from biting sick people. The Aedes mosquitoes that transmit Chikungunya breed in a wide variety of man-made containers which are common around human dwellings. These containers collect rainwater, and include discarded tires, flowerpots, old oil drums, animal water troughs, water storage vessels, and plastic food containers. These breeding sites can be eliminated by Draining water from coolers, tanks, barrels, drums and buckets, etc. Emptying coolers when not in use. Removing from the house all objects, e.g. plant saucers, etc. which have water collected in them. Chikungunya epidemics, with the high attack rate of CHIKV , affect a large number of people in a short period of time associated with early rain fall (early monsoon ) and this is also consistently seen in Bangladesh outbreak 2017. Pain, the most frequent clinical manifestation of Chikungunya, is difficult to control, compromising the quality of life, intense psychosocial and economic repercussions, causing a serious public health problem that requires a targeted approach. General physicians, Infectious disease specialists, Rheumatologist and other specialist, nurses, pain specialists, physiotherapists, social workers, and healthcare managers are required to overcome these challenges so that an explosive increase in CHIKV cases can be mitigated.Chikungunya is a vector-borne disease transmitted to humans by the bites of infected female mosquitoes which breed in clean water collections in containers, tanks, disposables, junk material in domestic and peri-domestic situations besides natural habitats like tree holes, plantations etc. These mosquitoes can be found biting throughout daylight hours, though there may be peaks of activity in the early morning and late afternoon. A high vector density is seen in the post monsoon season that enhances the transmission. It causes fever and severe joint pain . Other symptoms include muscle pain , headache, nausea , fatigue and rash . Joint pain is often debilitating and can vary in duration. Chikungunya is rarely fatal. Symptoms are generally self-limiting and last for 2–3 days. The disease shares some clinical signs with dengue and zika , and can be misdiagnosed in areas where they are common. Here is the Clinical features of Chikungunya virus infections compared with dengue virus infections. Several methods can be used for diagnosis. Serological tests, such as enzyme-linked immunosorbent assays ( ELISA ), may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibody levels are highest 3 to 5 weeks after the onset of illness and persist for about 2 months. Samples collected during the first week after the onset of symptoms should be tested by both serological and virological methods ( RT-PCR ). There is no vaccine to prevent or anti-viral drugs to treat Chikungunya virus. Treatment is directed primarily at relieving the symptoms, including the joint pain using anti-pyretics , optimal analgesics and fluids. In Bangladesh, the first recognized outbreak of Chikungunya was reported in 2008 in two villages in the northwest part of the country adjacent to Indian border. Two small-scale outbreaks were documented in rural communities in 2011 and 2012. A massive outbreak of Chikungunya occurred in Bangladesh during the period of April–September 2017 and over two million people at Dhaka, the capital of Bangladesh were at risk of getting infected by the virus. A recent research study (1326 cases) was conducted (between 24 July and 5 August 2017) to investigate the clinical profiles, economic burden, and quality of life of Chikungunya affected individuals. Severe arthropathy is the most consistent clinical feature of chikungunya infection. In this study, all patients experienced Arthalgia (100%); Pain before fever (74.66%); Skin Rash(69.6%); Itching (60.9%); Headache (77.3%) and Myalgia (69.3%) (Figure-2). Also,t he severity of certain clinical manifestations of Chikungunya might depend on several factors including age, gender, immune status, genetic predisposition and co-morbid conditions. Children (<15 years) tended to have a higher proportion of oligo-arthralgia and skin rash; while morning stiffness , severity, and duration of pain were proportionally lower among children as compared to other age groups. Joint swelling was most commonly noted in elderly patients (60+ years), while the severity of pain was highest among adults (30–59 years). Chikungunya infection caused significant loss of productivity due to absenteeism from job.Prevention is entirely dependent upon taking steps to avoid mosquito bites and elimination of mosquito breeding sites. Wear full sleeve clothes and long dresses to cover the limbs. Use mosquito coils, repellents and electric vapour mats during the daytime. Use mosquito nets – to protect babies, old people and others, who may rest during the day. The effectiveness of such nets can be improved by treating them with permethrin (pyrethroid insecticide). Mosquitoes become infected when they bite people who are sick with Chikungunya. Mosquito nets and mosquito coils will effectively prevent mosquitoes from biting sick people.The Aedes mosquitoes that transmit Chikungunya breed in a wide variety of man-made containers which are common around human dwellings. These containers collect rainwater, and include discarded tires, flowerpots, old oil drums, animal water troughs, water storage vessels, and plastic food containers. These breeding sites can be eliminated by Draining water from coolers, tanks, barrels, drums and buckets, etc. Emptying coolers when not in use. Removing from the house all objects, e.g. plant saucers, etc. which have water collected in them. Chikungunya epidemics, with the high attack rate of CHIKV , affect a large number of people in a short period of time associated with early rain fall (early monsoon ) and this is also consistently seen in Bangladesh outbreak 2017. Pain, the most frequent clinical manifestation of Chikungunya, is difficult to control, compromising the quality of life, intense psychosocial and economic repercussions, causing a serious public health problem that requires a targeted approach. General physicians, Infectious disease specialists, Rheumatologist and other specialist, nurses, pain specialists, physiotherapists, social workers, and healthcare managers are required to overcome these challenges so that an explosive increase in CHIKV cases can be mitigated.Bangladesh is battling its worst dengue outbreak on record. The health care system is straining because of high number of sick people and hospitals are facing a shortage of beds and staff to care for patients.Dengue was initially documented in 1960s, known as 'Dacca fever' at the time.Since 2010, incidences of dengue seem to align with the wet season spanning from May to September and high temperatures. The climate is increasingly becoming conducive to the spread of dengue due to heavy rainfall, waterlogging. floods, rising temperatures, and unexpected alterations in the country's seasons. Epidemiology of dengue in Bangladesh: Between January 1 and August 19, 2023, Bangladesh reported 97,476 cases of dengue, resulting in 466 deaths. This outbreak affected 37.6% women and 17.8% children under 18. The World Health Organization noted that dengue had spread to all 64 districts in Bangladesh. In Cox's Bazar, specific Rohingya camps were hotspots for dengue cases. It is estimated that around 80-90% people in Dhaka and Chittagong city had been infected with dengue in their lifetime. Causes of high dengue prevalence in Bangladesh: Rapidly growing and densely populated cities Unplanned urbanisation People store water in buckets, plastic containers and elsewhere because of water supply problem where mosquitoes can live all year round. Increasing number of high rise buildings with car parks in the basement where people wash their car, which is ideal for mosquitoes. Plenty of water lying around the construction sites. Aedes aegypti has developed resistance to insecticides like malathion. A cost-effective vaccine perhaps the best hope for Bangladesh. A promising single-dose vaccine developed by the US National Institutes of Health (Bethesda, MD, USA) in collaboration with the University of Vermont Vaccine Testing Center (Burlington, VT, USA) and Johns Hopkins University (Baltimore, MD, USA) is under clinical trial.

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Chikungunya

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Macrophage

Macrophages (abbreviated as M φ , MΦ or MP ) ( Greek : large eaters , from Greek μακρός ( makrós ) = large, φαγεῖν ( phagein ) = to eat) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells , microbes , cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis , which acts to defend the host against infection and injury. Macrophages are found in essentially all tissues, where they patrol for potential pathogens by amoeboid movement . They take various forms (with various names) throughout the body (e.g., histiocytes , Kupffer cells , alveolar macrophages , microglia , and others), but all are part of the mononuclear phagocyte system . Besides phagocytosis, they play a critical role in nonspecific defense ( innate immunity ) and also help initiate specific defense mechanisms ( adaptive immunity ) by recruiting other immune cells such as lymphocytes . For example, they are important as antigen presenters to T cells . In humans, dysfunctional macrophages cause severe diseases such as chronic granulomatous disease that result in frequent infections. Beyond increasing inflammation and stimulating the immune system, macrophages also play an important anti-inflammatory role and can decrease immune reactions through the release of cytokines . Macrophages that encourage inflammation are called M1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages. This difference is reflected in their metabolism; M1 macrophages have the unique ability to metabolize arginine to the "killer" molecule nitric oxide , whereas M2 macrophages have the unique ability to metabolize arginine to the "repair" molecule ornithine . However, this dichotomy has been recently questioned as further complexity has been discovered. Human macrophages are about 21 micrometres (0.00083 in) in diameter and are produced by the differentiation of monocytes in tissues. They can be identified using flow cytometry or immunohistochemical staining by their specific expression of proteins such as CD14 , CD40 , CD11b , CD64 , F4/80 (mice)/ EMR1 (human), lysozyme M, MAC-1 /MAC-3 and CD68 . Macrophages were first discovered and named by Élie Metchnikoff , a Russian Empire zoologist, in 1884. A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of foreign particles is likely to occur. These cells together as a group are known as the mononuclear phagocyte system and were previously known as the reticuloendothelial system. Each type of macrophage, determined by its location, has a specific name: Investigations concerning Kupffer cells are hampered because in humans, Kupffer cells are only accessible for immunohistochemical analysis from biopsies or autopsies. From rats and mice, they are difficult to isolate, and after purification, only approximately 5 million cells can be obtained from one mouse. Macrophages can express paracrine functions within organs :) that are specific to the function of that organ. In the testis , for example, macrophages have been shown to be able to interact with Leydig cells by secreting 25-hydroxycholesterol , an oxysterol that can be converted to testosterone by neighbouring Leydig cells. Also, testicular macrophages may participate in creating an immune privileged environment in the testis, and in mediating infertility during inflammation of the testis. Cardiac resident macrophages participate in electrical conduction via gap junction communication with cardiac myocytes . Macrophages can be classified on basis of the fundamental function and activation. According to this grouping, there are classically activated (M1) macrophages , wound-healing macrophages (also known as alternatively-activated (M2) macrophages ), and regulatory macrophages (Mregs). A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of foreign particles is likely to occur. These cells together as a group are known as the mononuclear phagocyte system and were previously known as the reticuloendothelial system. Each type of macrophage, determined by its location, has a specific name: Investigations concerning Kupffer cells are hampered because in humans, Kupffer cells are only accessible for immunohistochemical analysis from biopsies or autopsies. From rats and mice, they are difficult to isolate, and after purification, only approximately 5 million cells can be obtained from one mouse. Macrophages can express paracrine functions within organs :) that are specific to the function of that organ. In the testis , for example, macrophages have been shown to be able to interact with Leydig cells by secreting 25-hydroxycholesterol , an oxysterol that can be converted to testosterone by neighbouring Leydig cells. Also, testicular macrophages may participate in creating an immune privileged environment in the testis, and in mediating infertility during inflammation of the testis. Cardiac resident macrophages participate in electrical conduction via gap junction communication with cardiac myocytes . Macrophages can be classified on basis of the fundamental function and activation. According to this grouping, there are classically activated (M1) macrophages , wound-healing macrophages (also known as alternatively-activated (M2) macrophages ), and regulatory macrophages (Mregs). Macrophages that reside in adult healthy tissues either derive from circulating monocytes or are established before birth and then maintained during adult life independently of monocytes. By contrast, most of the macrophages that accumulate at diseased sites typically derive from circulating monocytes. Leukocyte extravasation describes monocyte entry into damaged tissue through the endothelium of blood vessels as they become macrophages. Monocytes are attracted to a damaged site by chemical substances through chemotaxis , triggered by a range of stimuli including damaged cells, pathogens and cytokines released by macrophages already at the site. At some sites such as the testis, macrophages have been shown to populate the organ through proliferation. Unlike short-lived neutrophils , macrophages survive longer in the body, up to several months.Macrophages are professional phagocytes and are highly specialized in removal of dying or dead cells and cellular debris. This role is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophils, which are ingested by macrophages if they come of age (see CD31 for a description of this process). The neutrophils are at first attracted to a site, where they perform their function and die, before they or their neutrophil extracellular traps are phagocytized by the macrophages. When at the site, the first wave of neutrophils, after the process of aging and after the first 48 hours, stimulate the appearance of the macrophages whereby these macrophages will then ingest the aged neutrophils. The removal of dying cells is, to a greater extent, handled by fixed macrophages , which will stay at strategic locations such as the lungs, liver, neural tissue , bone, spleen and connective tissue, ingesting foreign materials such as pathogens and recruiting additional macrophages if needed. When a macrophage ingests a pathogen, the pathogen becomes trapped in a phagosome , which then fuses with a lysosome . Within the phagolysosome , enzymes and toxic peroxides digest the pathogen. However, some bacteria, such as Mycobacterium tuberculosis , have become resistant to these methods of digestion. Typhoidal Salmonellae induce their own phagocytosis by host macrophages in vivo, and inhibit digestion by lysosomal action, thereby using macrophages for their own replication and causing macrophage apoptosis. Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds. When a pathogen invades, tissue resident macrophages are among the first cells to respond. Two of the main roles of the tissue resident macrophages are to phagocytose incoming antigen and to secrete proinflammatory cytokines that induce inflammation and recruit other immune cells to the site. Macrophages can internalize antigens through receptor-mediated phagocytosis. Macrophages have a wide variety of pattern recognition receptors (PRRs) that can recognize microbe-associated molecular patterns (MAMPs) from pathogens. Many PRRs, such as toll-like receptors (TLRs), scavenger receptors (SRs), C-type lectin receptors, among others, recognize pathogens for phagocytosis. Macrophages can also recognize pathogens for phagocytosis indirectly through opsonins , which are molecules that attach to pathogens and mark them for phagocytosis. Opsonins can cause a stronger adhesion between the macrophage and pathogen during phagocytosis, hence opsonins tend to enhance macrophages' phagocytic activity. Both complement proteins and antibodies can bind to antigens and opsonize them. Macrophages have complement receptor 1 (CR1) and 3 (CR3) that recognize pathogen-bound complement proteins C3b and iC3b, respectively, as well as fragment crystallizable γ receptors (FcγRs) that recognize the fragment crystallizable (Fc) region of antigen-bound immunoglobulin G (IgG) antibodies. When phagocytosing and digesting pathogens, macrophages go through a respiratory burst where more oxygen is consumed to supply the energy required for producing reactive oxygen species (ROS) and other antimicrobial molecules that digest the consumed pathogens. Recognition of MAMPs by PRRs can activate tissue resident macrophages to secrete proinflammatory cytokines that recruit other immune cells. Among the PRRs, TLRs play a major role in signal transduction leading to cytokine production. The binding of MAMPs to TLR triggers a series of downstream events that eventually activates transcription factor NF-κB and results in transcription of the genes for several proinflammatory cytokines, including IL-1β , IL-6 , TNF-α , IL-12B , and type I interferons such as IFN-α and IFN-β. Systemically, IL-1β, IL-6, and TNF-α induce fever and initiate the acute phase response in which the liver secretes acute phase proteins . Locally, IL-1β and TNF-α cause vasodilation, where the gaps between blood vessel epithelial cells widen, and upregulation of cell surface adhesion molecules on epithelial cells to induce leukocyte extravasation . Neutrophils are among the first immune cells recruited by macrophages to exit the blood via extravasation and arrive at the infection site. Macrophages secrete many chemokines such as CXCL1 , CXCL2 , and CXCL8 (IL-8) that attract neutrophils to the site of infection. After neutrophils have finished phagocytosing and clearing the antigen at the end of the immune response, they undergo apoptosis, and macrophages are recruited from blood monocytes to help clear apoptotic debris. Macrophages also recruit other immune cells such as monocytes, dendritic cells, natural killer cells, basophils, eosinophils, and T cells through chemokines such as CCL2 , CCL4 , CCL5 , CXCL8 , CXCL9 , CXCL10 , and CXCL11 . Along with dendritic cells, macrophages help activate natural killer (NK) cells through secretion of type I interferons (IFN-α and IFN-β) and IL-12 . IL-12 acts with IL-18 to stimulate the production of proinflammatory cytokine interferon gamma (IFN-γ) by NK cells, which serves as an important source of IFN-γ before the adaptive immune system is activated. IFN-γ enhances the innate immune response by inducing a more aggressive phenotype in macrophages, allowing macrophages to more efficiently kill pathogens. Some of the T cell chemoattractants secreted by macrophages include CCL5 , CXCL9 , CXCL10 , and CXCL11 . Macrophages are professional antigen presenting cells (APC), meaning they can present peptides from phagocytosed antigens on major histocompatibility complex (MHC) II molecules on their cell surface for T helper cells. Macrophages are not primary activators of naïve T helper cells that have never been previously activated since tissue resident macrophages do not travel to the lymph nodes where naïve T helper cells reside. Although macrophages are also found in secondary lymphoid organs like the lymph nodes, they do not reside in T cell zones and are not effective at activating naïve T helper cells. The macrophages in lymphoid tissues are more involved in ingesting antigens and preventing them from entering the blood, as well as taking up debris from apoptotic lymphocytes. Therefore, macrophages interact mostly with previously activated T helper cells that have left the lymph node and arrived at the site of infection or with tissue resident memory T cells. Macrophages supply both signals required for T helper cell activation: 1) Macrophages present antigen peptide-bound MHC class II molecule to be recognized by the corresponding T cell receptor (TCR), and 2) recognition of pathogens by PRRs induce macrophages to upregulate the co-stimulatory molecules CD80 and CD86 (also known as B7 ) that binds to CD28 on T helper cells to supply the co-stimulatory signal. These interactions allow T helper cells to achieve full effector function and provide T helper cells with continued survival and differentiation signals preventing them from undergoing apoptosis due to lack of TCR signaling. For example, IL-2 signaling in T cells upregulates the expression of anti-apoptotic protein Bcl-2 , but T cell production of IL-2 and the high-affinity IL-2 receptor IL-2RA both require continued signal from TCR recognition of MHC-bound antigen. Macrophages can achieve different activation phenotypes through interactions with different subsets of T helper cells, such as T H 1 and T H 2. Although there is a broad spectrum of macrophage activation phenotypes, there are two major phenotypes that are commonly acknowledged. They are the classically activated macrophages, or M1 macrophages, and the alternatively activated macrophages, or M2 macrophages. M1 macrophages are proinflammatory, while M2 macrophages are mostly anti-inflammatory. T H 1 cells play an important role in classical macrophage activation as part of type 1 immune response against intracellular pathogens (such as intracellular bacteria ) that can survive and replicate inside host cells, especially those pathogens that replicate even after being phagocytosed by macrophages. After the TCR of T H 1 cells recognize specific antigen peptide-bound MHC class II molecules on macrophages, T H 1 cells 1) secrete IFN-γ and 2) upregulate the expression of CD40 ligand (CD40L), which binds to CD40 on macrophages. These 2 signals activate the macrophages and enhance their ability to kill intracellular pathogens through increased production of antimicrobial molecules such as nitric oxide (NO) and superoxide (O 2- ). This enhancement of macrophages' antimicrobial ability by T H 1 cells is known as classical macrophage activation, and the activated macrophages are known as classically activated macrophages, or M1 macrophages. The M1 macrophages in turn upregulates B7 molecules and antigen presentation through MHC class II molecules to provide signals that sustain T cell help. The activation of T H 1 and M1 macrophage is a positive feedback loop, with IFN-γ from T H 1 cells upregulating CD40 expression on macrophages; the interaction between CD40 on the macrophages and CD40L on T cells activate macrophages to secrete IL-12; and IL-12 promotes more IFN-γ secretion from T H 1 cells. The initial contact between macrophage antigen-bound MHC II and TCR serves as the contact point between the two cells where most of the IFN-γ secretion and CD-40L on T cells concentrate to, so only macrophages directly interacting with T H 1 cells are likely to be activated. In addition to activating M1 macrophages, T H 1 cells express Fas ligand (FasL) and lymphotoxin beta (LT-β) to help kill chronically infected macrophages that can no longer kill pathogens. The killing of chronically infected macrophages release pathogens to the extracellular space that can then be killed by other activated macrophages. T H 1 cells also help recruit more monocytes, the precursor to macrophages, to the infection site. T H 1 secretion TNF-α and LT-α to make blood vessels easier for monocytes to bind to and exit. T H 1 secretion of CCL2 as a chemoattractant for monocytes. IL-3 and GM-CSF released by T H 1 cells stimulate more monocyte production in the bone marrow. When intracellular pathogens cannot be eliminated, such as in the case of Mycobacterium tuberculosis , the pathogen is contained through the formation of granuloma , an aggregation of infected macrophages surrounded by activated T cells. The macrophages bordering the activated lymphocytes often fuse to form multinucleated giant cells that appear to have increased antimicrobial ability due to their proximity to T H 1 cells, but over time, the cells in the center start to die and form necrotic tissue. T H 2 cells play an important role in alternative macrophage activation as part of type 2 immune response against large extracellular pathogens like helminths . T H 2 cells secrete IL-4 and IL-13, which activate macrophages to become M2 macrophages, also known as alternatively activated macrophages. M2 macrophages express arginase-1 , an enzyme that converts arginine to ornithine and urea . Ornithine help increase smooth muscle contraction to expel the worm and also participates in tissue and wound repair. Ornithine can be further metabolized to proline , which is essential for synthesizing collagen . M2 macrophages can also decrease inflammation by producing IL-1 receptor antagonist (IL-1RA) and IL-1 receptors that do not lead to downstream inflammatory signaling (IL-1RII). Another part of the adaptive immunity activation involves stimulating CD8 + via cross presentation of antigens peptides on MHC class I molecules. Studies have shown that proinflammatory macrophages are capable of cross presentation of antigens on MHC class I molecules, but whether macrophage cross-presentation plays a role in naïve or memory CD8 + T cell activation is still unclear. Macrophages have been shown to secrete cytokines BAFF and APRIL, which are important for plasma cell isotype switching. APRIL and IL-6 secreted by macrophage precursors in the bone marrow help maintain survival of plasma cells homed to the bone marrow. There are several activated forms of macrophages. In spite of a spectrum of ways to activate macrophages, there are two main groups designated M1 and M2 . M1 macrophages: as mentioned earlier (previously referred to as classically activated macrophages), M1 "killer" macrophages are activated by LPS and IFN-gamma , and secrete high levels of IL-12 and low levels of IL-10 . M1 macrophages have pro-inflammatory, bactericidal, and phagocytic functions. In contrast, the M2 "repair" designation (also referred to as alternatively activated macrophages) broadly refers to macrophages that function in constructive processes like wound healing and tissue repair, and those that turn off damaging immune system activation by producing anti-inflammatory cytokines like IL-10 . M2 is the phenotype of resident tissue macrophages, and can be further elevated by IL-4 . M2 macrophages produce high levels of IL-10, TGF-beta and low levels of IL-12. Tumor-associated macrophages are mainly of the M2 phenotype, and seem to actively promote tumor growth. Macrophages exist in a variety of phenotypes which are determined by the role they play in wound maturation. Phenotypes can be predominantly separated into two major categories; M1 and M2. M1 macrophages are the dominating phenotype observed in the early stages of inflammation and are activated by four key mediators: interferon-γ (IFN-γ), tumor necrosis factor (TNF), and damage associated molecular patterns (DAMPs). These mediator molecules create a pro-inflammatory response that in return produce pro-inflammatory cytokines like Interleukin-6 and TNF. Unlike M1 macrophages, M2 macrophages secrete an anti-inflammatory response via the addition of Interleukin-4 or Interleukin-13. They also play a role in wound healing and are needed for revascularization and reepithelialization. M2 macrophages are divided into four major types based on their roles: M2a, M2b, M2c, and M2d. How M2 phenotypes are determined is still up for discussion but studies have shown that their environment allows them to adjust to whichever phenotype is most appropriate to efficiently heal the wound. M2 macrophages are needed for vascular stability. They produce vascular endothelial growth factor-A and TGF-β1 . There is a phenotype shift from M1 to M2 macrophages in acute wounds, however this shift is impaired for chronic wounds. This dysregulation results in insufficient M2 macrophages and its corresponding growth factors that aid in wound repair. With a lack of these growth factors/anti-inflammatory cytokines and an overabundance of pro-inflammatory cytokines from M1 macrophages chronic wounds are unable to heal in a timely manner. Normally, after neutrophils eat debris/pathogens they perform apoptosis and are removed. At this point, inflammation is not needed and M1 undergoes a switch to M2 (anti-inflammatory). However, dysregulation occurs as the M1 macrophages are unable/do not phagocytose neutrophils that have undergone apoptosis leading to increased macrophage migration and inflammation. Both M1 and M2 macrophages play a role in promotion of atherosclerosis . M1 macrophages promote atherosclerosis by inflammation. M2 macrophages can remove cholesterol from blood vessels, but when the cholesterol is oxidized, the M2 macrophages become apoptotic foam cells contributing to the atheromatous plaque of atherosclerosis. The first step to understanding the importance of macrophages in muscle repair, growth, and regeneration is that there are two "waves" of macrophages with the onset of damageable muscle use– subpopulations that do and do not directly have an influence on repairing muscle. The initial wave is a phagocytic population that comes along during periods of increased muscle use that are sufficient to cause muscle membrane lysis and membrane inflammation, which can enter and degrade the contents of injured muscle fibers. These early-invading, phagocytic macrophages reach their highest concentration about 24 hours following the onset of some form of muscle cell injury or reloading. Their concentration rapidly declines after 48 hours. The second group is the non-phagocytic types that are distributed near regenerative fibers. These peak between two and four days and remain elevated for several days during while muscle tissue is rebuilding. The first subpopulation has no direct benefit to repairing muscle, while the second non-phagocytic group does. It is thought that macrophages release soluble substances that influence the proliferation, differentiation, growth, repair, and regeneration of muscle, but at this time the factor that is produced to mediate these effects is unknown. It is known that macrophages' involvement in promoting tissue repair is not muscle specific; they accumulate in numerous tissues during the healing process phase following injury. Macrophages are essential for wound healing . They replace polymorphonuclear neutrophils as the predominant cells in the wound by day two after injury. Attracted to the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enter the area through blood vessel walls. Numbers of monocytes in the wound peak one to one and a half days after the injury occurs. Once they are in the wound site, monocytes mature into macrophages. The spleen contains half the body's monocytes in reserve ready to be deployed to injured tissue. The macrophage's main role is to phagocytize bacteria and damaged tissue, and they also debride damaged tissue by releasing proteases. Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wound days. These factors attract cells involved in the proliferation stage of healing to the area. Macrophages may also restrain the contraction phase. Macrophages are stimulated by the low oxygen content of their surroundings to produce factors that induce and speed angiogenesis and they also stimulate cells that re-epithelialize the wound, create granulation tissue, and lay down a new extracellular matrix . [ better source needed ] By secreting these factors, macrophages contribute to pushing the wound healing process into the next phase. Scientists have elucidated that as well as eating up material debris, macrophages are involved in the typical limb regeneration in the salamander. They found that removing the macrophages from a salamander resulted in failure of limb regeneration and a scarring response. As described above, macrophages play a key role in removing dying or dead cells and cellular debris. Erythrocytes have a lifespan on average of 120 days and so are constantly being destroyed by macrophages in the spleen and liver. Macrophages will also engulf macromolecules , and so play a key role in the pharmacokinetics of parenteral irons . [ citation needed ] The iron that is released from the haemoglobin is either stored internally in ferritin or is released into the circulation via ferroportin . In cases where systemic iron levels are raised, or where inflammation is present, raised levels of hepcidin act on macrophage ferroportin channels, leading to iron remaining within the macrophages. [ citation needed ] Melanophages are a subset of tissue-resident macrophages able to absorb pigment, either native to the organism or exogenous (such as tattoos ), from extracellular space. In contrast to dendritic juncional melanocytes , which synthesize melanosomes and contain various stages of their development, the melanophages only accumulate phagocytosed melanin in lysosome-like phagosomes. This occurs repeatedly as the pigment from dead dermal macrophages is phagocytosed by their successors, preserving the tattoo in the same place. Every tissue harbors its own specialized population of resident macrophages, which entertain reciprocal interconnections with the stroma and functional tissue. These resident macrophages are sessile (non-migratory), provide essential growth factors to support the physiological function of the tissue (e.g. macrophage-neuronal crosstalk in the guts), and can actively protect the tissue from inflammatory damage. Nerve-associated macrophages or NAMs are those tissue-resident macrophages that are associated with nerves. Some of them are known to have an elongated morphology of up to 200μm Macrophages are professional phagocytes and are highly specialized in removal of dying or dead cells and cellular debris. This role is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophils, which are ingested by macrophages if they come of age (see CD31 for a description of this process). The neutrophils are at first attracted to a site, where they perform their function and die, before they or their neutrophil extracellular traps are phagocytized by the macrophages. When at the site, the first wave of neutrophils, after the process of aging and after the first 48 hours, stimulate the appearance of the macrophages whereby these macrophages will then ingest the aged neutrophils. The removal of dying cells is, to a greater extent, handled by fixed macrophages , which will stay at strategic locations such as the lungs, liver, neural tissue , bone, spleen and connective tissue, ingesting foreign materials such as pathogens and recruiting additional macrophages if needed. When a macrophage ingests a pathogen, the pathogen becomes trapped in a phagosome , which then fuses with a lysosome . Within the phagolysosome , enzymes and toxic peroxides digest the pathogen. However, some bacteria, such as Mycobacterium tuberculosis , have become resistant to these methods of digestion. Typhoidal Salmonellae induce their own phagocytosis by host macrophages in vivo, and inhibit digestion by lysosomal action, thereby using macrophages for their own replication and causing macrophage apoptosis. Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds.When a pathogen invades, tissue resident macrophages are among the first cells to respond. Two of the main roles of the tissue resident macrophages are to phagocytose incoming antigen and to secrete proinflammatory cytokines that induce inflammation and recruit other immune cells to the site. Macrophages can internalize antigens through receptor-mediated phagocytosis. Macrophages have a wide variety of pattern recognition receptors (PRRs) that can recognize microbe-associated molecular patterns (MAMPs) from pathogens. Many PRRs, such as toll-like receptors (TLRs), scavenger receptors (SRs), C-type lectin receptors, among others, recognize pathogens for phagocytosis. Macrophages can also recognize pathogens for phagocytosis indirectly through opsonins , which are molecules that attach to pathogens and mark them for phagocytosis. Opsonins can cause a stronger adhesion between the macrophage and pathogen during phagocytosis, hence opsonins tend to enhance macrophages' phagocytic activity. Both complement proteins and antibodies can bind to antigens and opsonize them. Macrophages have complement receptor 1 (CR1) and 3 (CR3) that recognize pathogen-bound complement proteins C3b and iC3b, respectively, as well as fragment crystallizable γ receptors (FcγRs) that recognize the fragment crystallizable (Fc) region of antigen-bound immunoglobulin G (IgG) antibodies. When phagocytosing and digesting pathogens, macrophages go through a respiratory burst where more oxygen is consumed to supply the energy required for producing reactive oxygen species (ROS) and other antimicrobial molecules that digest the consumed pathogens. Recognition of MAMPs by PRRs can activate tissue resident macrophages to secrete proinflammatory cytokines that recruit other immune cells. Among the PRRs, TLRs play a major role in signal transduction leading to cytokine production. The binding of MAMPs to TLR triggers a series of downstream events that eventually activates transcription factor NF-κB and results in transcription of the genes for several proinflammatory cytokines, including IL-1β , IL-6 , TNF-α , IL-12B , and type I interferons such as IFN-α and IFN-β. Systemically, IL-1β, IL-6, and TNF-α induce fever and initiate the acute phase response in which the liver secretes acute phase proteins . Locally, IL-1β and TNF-α cause vasodilation, where the gaps between blood vessel epithelial cells widen, and upregulation of cell surface adhesion molecules on epithelial cells to induce leukocyte extravasation . Neutrophils are among the first immune cells recruited by macrophages to exit the blood via extravasation and arrive at the infection site. Macrophages secrete many chemokines such as CXCL1 , CXCL2 , and CXCL8 (IL-8) that attract neutrophils to the site of infection. After neutrophils have finished phagocytosing and clearing the antigen at the end of the immune response, they undergo apoptosis, and macrophages are recruited from blood monocytes to help clear apoptotic debris. Macrophages also recruit other immune cells such as monocytes, dendritic cells, natural killer cells, basophils, eosinophils, and T cells through chemokines such as CCL2 , CCL4 , CCL5 , CXCL8 , CXCL9 , CXCL10 , and CXCL11 . Along with dendritic cells, macrophages help activate natural killer (NK) cells through secretion of type I interferons (IFN-α and IFN-β) and IL-12 . IL-12 acts with IL-18 to stimulate the production of proinflammatory cytokine interferon gamma (IFN-γ) by NK cells, which serves as an important source of IFN-γ before the adaptive immune system is activated. IFN-γ enhances the innate immune response by inducing a more aggressive phenotype in macrophages, allowing macrophages to more efficiently kill pathogens. Some of the T cell chemoattractants secreted by macrophages include CCL5 , CXCL9 , CXCL10 , and CXCL11 . Macrophages can internalize antigens through receptor-mediated phagocytosis. Macrophages have a wide variety of pattern recognition receptors (PRRs) that can recognize microbe-associated molecular patterns (MAMPs) from pathogens. Many PRRs, such as toll-like receptors (TLRs), scavenger receptors (SRs), C-type lectin receptors, among others, recognize pathogens for phagocytosis. Macrophages can also recognize pathogens for phagocytosis indirectly through opsonins , which are molecules that attach to pathogens and mark them for phagocytosis. Opsonins can cause a stronger adhesion between the macrophage and pathogen during phagocytosis, hence opsonins tend to enhance macrophages' phagocytic activity. Both complement proteins and antibodies can bind to antigens and opsonize them. Macrophages have complement receptor 1 (CR1) and 3 (CR3) that recognize pathogen-bound complement proteins C3b and iC3b, respectively, as well as fragment crystallizable γ receptors (FcγRs) that recognize the fragment crystallizable (Fc) region of antigen-bound immunoglobulin G (IgG) antibodies. When phagocytosing and digesting pathogens, macrophages go through a respiratory burst where more oxygen is consumed to supply the energy required for producing reactive oxygen species (ROS) and other antimicrobial molecules that digest the consumed pathogens. Recognition of MAMPs by PRRs can activate tissue resident macrophages to secrete proinflammatory cytokines that recruit other immune cells. Among the PRRs, TLRs play a major role in signal transduction leading to cytokine production. The binding of MAMPs to TLR triggers a series of downstream events that eventually activates transcription factor NF-κB and results in transcription of the genes for several proinflammatory cytokines, including IL-1β , IL-6 , TNF-α , IL-12B , and type I interferons such as IFN-α and IFN-β. Systemically, IL-1β, IL-6, and TNF-α induce fever and initiate the acute phase response in which the liver secretes acute phase proteins . Locally, IL-1β and TNF-α cause vasodilation, where the gaps between blood vessel epithelial cells widen, and upregulation of cell surface adhesion molecules on epithelial cells to induce leukocyte extravasation . Neutrophils are among the first immune cells recruited by macrophages to exit the blood via extravasation and arrive at the infection site. Macrophages secrete many chemokines such as CXCL1 , CXCL2 , and CXCL8 (IL-8) that attract neutrophils to the site of infection. After neutrophils have finished phagocytosing and clearing the antigen at the end of the immune response, they undergo apoptosis, and macrophages are recruited from blood monocytes to help clear apoptotic debris. Macrophages also recruit other immune cells such as monocytes, dendritic cells, natural killer cells, basophils, eosinophils, and T cells through chemokines such as CCL2 , CCL4 , CCL5 , CXCL8 , CXCL9 , CXCL10 , and CXCL11 . Along with dendritic cells, macrophages help activate natural killer (NK) cells through secretion of type I interferons (IFN-α and IFN-β) and IL-12 . IL-12 acts with IL-18 to stimulate the production of proinflammatory cytokine interferon gamma (IFN-γ) by NK cells, which serves as an important source of IFN-γ before the adaptive immune system is activated. IFN-γ enhances the innate immune response by inducing a more aggressive phenotype in macrophages, allowing macrophages to more efficiently kill pathogens. Some of the T cell chemoattractants secreted by macrophages include CCL5 , CXCL9 , CXCL10 , and CXCL11 . Macrophages are professional antigen presenting cells (APC), meaning they can present peptides from phagocytosed antigens on major histocompatibility complex (MHC) II molecules on their cell surface for T helper cells. Macrophages are not primary activators of naïve T helper cells that have never been previously activated since tissue resident macrophages do not travel to the lymph nodes where naïve T helper cells reside. Although macrophages are also found in secondary lymphoid organs like the lymph nodes, they do not reside in T cell zones and are not effective at activating naïve T helper cells. The macrophages in lymphoid tissues are more involved in ingesting antigens and preventing them from entering the blood, as well as taking up debris from apoptotic lymphocytes. Therefore, macrophages interact mostly with previously activated T helper cells that have left the lymph node and arrived at the site of infection or with tissue resident memory T cells. Macrophages supply both signals required for T helper cell activation: 1) Macrophages present antigen peptide-bound MHC class II molecule to be recognized by the corresponding T cell receptor (TCR), and 2) recognition of pathogens by PRRs induce macrophages to upregulate the co-stimulatory molecules CD80 and CD86 (also known as B7 ) that binds to CD28 on T helper cells to supply the co-stimulatory signal. These interactions allow T helper cells to achieve full effector function and provide T helper cells with continued survival and differentiation signals preventing them from undergoing apoptosis due to lack of TCR signaling. For example, IL-2 signaling in T cells upregulates the expression of anti-apoptotic protein Bcl-2 , but T cell production of IL-2 and the high-affinity IL-2 receptor IL-2RA both require continued signal from TCR recognition of MHC-bound antigen. Macrophages can achieve different activation phenotypes through interactions with different subsets of T helper cells, such as T H 1 and T H 2. Although there is a broad spectrum of macrophage activation phenotypes, there are two major phenotypes that are commonly acknowledged. They are the classically activated macrophages, or M1 macrophages, and the alternatively activated macrophages, or M2 macrophages. M1 macrophages are proinflammatory, while M2 macrophages are mostly anti-inflammatory. T H 1 cells play an important role in classical macrophage activation as part of type 1 immune response against intracellular pathogens (such as intracellular bacteria ) that can survive and replicate inside host cells, especially those pathogens that replicate even after being phagocytosed by macrophages. After the TCR of T H 1 cells recognize specific antigen peptide-bound MHC class II molecules on macrophages, T H 1 cells 1) secrete IFN-γ and 2) upregulate the expression of CD40 ligand (CD40L), which binds to CD40 on macrophages. These 2 signals activate the macrophages and enhance their ability to kill intracellular pathogens through increased production of antimicrobial molecules such as nitric oxide (NO) and superoxide (O 2- ). This enhancement of macrophages' antimicrobial ability by T H 1 cells is known as classical macrophage activation, and the activated macrophages are known as classically activated macrophages, or M1 macrophages. The M1 macrophages in turn upregulates B7 molecules and antigen presentation through MHC class II molecules to provide signals that sustain T cell help. The activation of T H 1 and M1 macrophage is a positive feedback loop, with IFN-γ from T H 1 cells upregulating CD40 expression on macrophages; the interaction between CD40 on the macrophages and CD40L on T cells activate macrophages to secrete IL-12; and IL-12 promotes more IFN-γ secretion from T H 1 cells. The initial contact between macrophage antigen-bound MHC II and TCR serves as the contact point between the two cells where most of the IFN-γ secretion and CD-40L on T cells concentrate to, so only macrophages directly interacting with T H 1 cells are likely to be activated. In addition to activating M1 macrophages, T H 1 cells express Fas ligand (FasL) and lymphotoxin beta (LT-β) to help kill chronically infected macrophages that can no longer kill pathogens. The killing of chronically infected macrophages release pathogens to the extracellular space that can then be killed by other activated macrophages. T H 1 cells also help recruit more monocytes, the precursor to macrophages, to the infection site. T H 1 secretion TNF-α and LT-α to make blood vessels easier for monocytes to bind to and exit. T H 1 secretion of CCL2 as a chemoattractant for monocytes. IL-3 and GM-CSF released by T H 1 cells stimulate more monocyte production in the bone marrow. When intracellular pathogens cannot be eliminated, such as in the case of Mycobacterium tuberculosis , the pathogen is contained through the formation of granuloma , an aggregation of infected macrophages surrounded by activated T cells. The macrophages bordering the activated lymphocytes often fuse to form multinucleated giant cells that appear to have increased antimicrobial ability due to their proximity to T H 1 cells, but over time, the cells in the center start to die and form necrotic tissue. T H 2 cells play an important role in alternative macrophage activation as part of type 2 immune response against large extracellular pathogens like helminths . T H 2 cells secrete IL-4 and IL-13, which activate macrophages to become M2 macrophages, also known as alternatively activated macrophages. M2 macrophages express arginase-1 , an enzyme that converts arginine to ornithine and urea . Ornithine help increase smooth muscle contraction to expel the worm and also participates in tissue and wound repair. Ornithine can be further metabolized to proline , which is essential for synthesizing collagen . M2 macrophages can also decrease inflammation by producing IL-1 receptor antagonist (IL-1RA) and IL-1 receptors that do not lead to downstream inflammatory signaling (IL-1RII). Another part of the adaptive immunity activation involves stimulating CD8 + via cross presentation of antigens peptides on MHC class I molecules. Studies have shown that proinflammatory macrophages are capable of cross presentation of antigens on MHC class I molecules, but whether macrophage cross-presentation plays a role in naïve or memory CD8 + T cell activation is still unclear. Macrophages have been shown to secrete cytokines BAFF and APRIL, which are important for plasma cell isotype switching. APRIL and IL-6 secreted by macrophage precursors in the bone marrow help maintain survival of plasma cells homed to the bone marrow. There are several activated forms of macrophages. In spite of a spectrum of ways to activate macrophages, there are two main groups designated M1 and M2 . M1 macrophages: as mentioned earlier (previously referred to as classically activated macrophages), M1 "killer" macrophages are activated by LPS and IFN-gamma , and secrete high levels of IL-12 and low levels of IL-10 . M1 macrophages have pro-inflammatory, bactericidal, and phagocytic functions. In contrast, the M2 "repair" designation (also referred to as alternatively activated macrophages) broadly refers to macrophages that function in constructive processes like wound healing and tissue repair, and those that turn off damaging immune system activation by producing anti-inflammatory cytokines like IL-10 . M2 is the phenotype of resident tissue macrophages, and can be further elevated by IL-4 . M2 macrophages produce high levels of IL-10, TGF-beta and low levels of IL-12. Tumor-associated macrophages are mainly of the M2 phenotype, and seem to actively promote tumor growth. Macrophages exist in a variety of phenotypes which are determined by the role they play in wound maturation. Phenotypes can be predominantly separated into two major categories; M1 and M2. M1 macrophages are the dominating phenotype observed in the early stages of inflammation and are activated by four key mediators: interferon-γ (IFN-γ), tumor necrosis factor (TNF), and damage associated molecular patterns (DAMPs). These mediator molecules create a pro-inflammatory response that in return produce pro-inflammatory cytokines like Interleukin-6 and TNF. Unlike M1 macrophages, M2 macrophages secrete an anti-inflammatory response via the addition of Interleukin-4 or Interleukin-13. They also play a role in wound healing and are needed for revascularization and reepithelialization. M2 macrophages are divided into four major types based on their roles: M2a, M2b, M2c, and M2d. How M2 phenotypes are determined is still up for discussion but studies have shown that their environment allows them to adjust to whichever phenotype is most appropriate to efficiently heal the wound. M2 macrophages are needed for vascular stability. They produce vascular endothelial growth factor-A and TGF-β1 . There is a phenotype shift from M1 to M2 macrophages in acute wounds, however this shift is impaired for chronic wounds. This dysregulation results in insufficient M2 macrophages and its corresponding growth factors that aid in wound repair. With a lack of these growth factors/anti-inflammatory cytokines and an overabundance of pro-inflammatory cytokines from M1 macrophages chronic wounds are unable to heal in a timely manner. Normally, after neutrophils eat debris/pathogens they perform apoptosis and are removed. At this point, inflammation is not needed and M1 undergoes a switch to M2 (anti-inflammatory). However, dysregulation occurs as the M1 macrophages are unable/do not phagocytose neutrophils that have undergone apoptosis leading to increased macrophage migration and inflammation. Both M1 and M2 macrophages play a role in promotion of atherosclerosis . M1 macrophages promote atherosclerosis by inflammation. M2 macrophages can remove cholesterol from blood vessels, but when the cholesterol is oxidized, the M2 macrophages become apoptotic foam cells contributing to the atheromatous plaque of atherosclerosis. Macrophages are professional antigen presenting cells (APC), meaning they can present peptides from phagocytosed antigens on major histocompatibility complex (MHC) II molecules on their cell surface for T helper cells. Macrophages are not primary activators of naïve T helper cells that have never been previously activated since tissue resident macrophages do not travel to the lymph nodes where naïve T helper cells reside. Although macrophages are also found in secondary lymphoid organs like the lymph nodes, they do not reside in T cell zones and are not effective at activating naïve T helper cells. The macrophages in lymphoid tissues are more involved in ingesting antigens and preventing them from entering the blood, as well as taking up debris from apoptotic lymphocytes. Therefore, macrophages interact mostly with previously activated T helper cells that have left the lymph node and arrived at the site of infection or with tissue resident memory T cells. Macrophages supply both signals required for T helper cell activation: 1) Macrophages present antigen peptide-bound MHC class II molecule to be recognized by the corresponding T cell receptor (TCR), and 2) recognition of pathogens by PRRs induce macrophages to upregulate the co-stimulatory molecules CD80 and CD86 (also known as B7 ) that binds to CD28 on T helper cells to supply the co-stimulatory signal. These interactions allow T helper cells to achieve full effector function and provide T helper cells with continued survival and differentiation signals preventing them from undergoing apoptosis due to lack of TCR signaling. For example, IL-2 signaling in T cells upregulates the expression of anti-apoptotic protein Bcl-2 , but T cell production of IL-2 and the high-affinity IL-2 receptor IL-2RA both require continued signal from TCR recognition of MHC-bound antigen. Macrophages can achieve different activation phenotypes through interactions with different subsets of T helper cells, such as T H 1 and T H 2. Although there is a broad spectrum of macrophage activation phenotypes, there are two major phenotypes that are commonly acknowledged. They are the classically activated macrophages, or M1 macrophages, and the alternatively activated macrophages, or M2 macrophages. M1 macrophages are proinflammatory, while M2 macrophages are mostly anti-inflammatory. T H 1 cells play an important role in classical macrophage activation as part of type 1 immune response against intracellular pathogens (such as intracellular bacteria ) that can survive and replicate inside host cells, especially those pathogens that replicate even after being phagocytosed by macrophages. After the TCR of T H 1 cells recognize specific antigen peptide-bound MHC class II molecules on macrophages, T H 1 cells 1) secrete IFN-γ and 2) upregulate the expression of CD40 ligand (CD40L), which binds to CD40 on macrophages. These 2 signals activate the macrophages and enhance their ability to kill intracellular pathogens through increased production of antimicrobial molecules such as nitric oxide (NO) and superoxide (O 2- ). This enhancement of macrophages' antimicrobial ability by T H 1 cells is known as classical macrophage activation, and the activated macrophages are known as classically activated macrophages, or M1 macrophages. The M1 macrophages in turn upregulates B7 molecules and antigen presentation through MHC class II molecules to provide signals that sustain T cell help. The activation of T H 1 and M1 macrophage is a positive feedback loop, with IFN-γ from T H 1 cells upregulating CD40 expression on macrophages; the interaction between CD40 on the macrophages and CD40L on T cells activate macrophages to secrete IL-12; and IL-12 promotes more IFN-γ secretion from T H 1 cells. The initial contact between macrophage antigen-bound MHC II and TCR serves as the contact point between the two cells where most of the IFN-γ secretion and CD-40L on T cells concentrate to, so only macrophages directly interacting with T H 1 cells are likely to be activated. In addition to activating M1 macrophages, T H 1 cells express Fas ligand (FasL) and lymphotoxin beta (LT-β) to help kill chronically infected macrophages that can no longer kill pathogens. The killing of chronically infected macrophages release pathogens to the extracellular space that can then be killed by other activated macrophages. T H 1 cells also help recruit more monocytes, the precursor to macrophages, to the infection site. T H 1 secretion TNF-α and LT-α to make blood vessels easier for monocytes to bind to and exit. T H 1 secretion of CCL2 as a chemoattractant for monocytes. IL-3 and GM-CSF released by T H 1 cells stimulate more monocyte production in the bone marrow. When intracellular pathogens cannot be eliminated, such as in the case of Mycobacterium tuberculosis , the pathogen is contained through the formation of granuloma , an aggregation of infected macrophages surrounded by activated T cells. The macrophages bordering the activated lymphocytes often fuse to form multinucleated giant cells that appear to have increased antimicrobial ability due to their proximity to T H 1 cells, but over time, the cells in the center start to die and form necrotic tissue. T H 2 cells play an important role in alternative macrophage activation as part of type 2 immune response against large extracellular pathogens like helminths . T H 2 cells secrete IL-4 and IL-13, which activate macrophages to become M2 macrophages, also known as alternatively activated macrophages. M2 macrophages express arginase-1 , an enzyme that converts arginine to ornithine and urea . Ornithine help increase smooth muscle contraction to expel the worm and also participates in tissue and wound repair. Ornithine can be further metabolized to proline , which is essential for synthesizing collagen . M2 macrophages can also decrease inflammation by producing IL-1 receptor antagonist (IL-1RA) and IL-1 receptors that do not lead to downstream inflammatory signaling (IL-1RII). T H 1 cells play an important role in classical macrophage activation as part of type 1 immune response against intracellular pathogens (such as intracellular bacteria ) that can survive and replicate inside host cells, especially those pathogens that replicate even after being phagocytosed by macrophages. After the TCR of T H 1 cells recognize specific antigen peptide-bound MHC class II molecules on macrophages, T H 1 cells 1) secrete IFN-γ and 2) upregulate the expression of CD40 ligand (CD40L), which binds to CD40 on macrophages. These 2 signals activate the macrophages and enhance their ability to kill intracellular pathogens through increased production of antimicrobial molecules such as nitric oxide (NO) and superoxide (O 2- ). This enhancement of macrophages' antimicrobial ability by T H 1 cells is known as classical macrophage activation, and the activated macrophages are known as classically activated macrophages, or M1 macrophages. The M1 macrophages in turn upregulates B7 molecules and antigen presentation through MHC class II molecules to provide signals that sustain T cell help. The activation of T H 1 and M1 macrophage is a positive feedback loop, with IFN-γ from T H 1 cells upregulating CD40 expression on macrophages; the interaction between CD40 on the macrophages and CD40L on T cells activate macrophages to secrete IL-12; and IL-12 promotes more IFN-γ secretion from T H 1 cells. The initial contact between macrophage antigen-bound MHC II and TCR serves as the contact point between the two cells where most of the IFN-γ secretion and CD-40L on T cells concentrate to, so only macrophages directly interacting with T H 1 cells are likely to be activated. In addition to activating M1 macrophages, T H 1 cells express Fas ligand (FasL) and lymphotoxin beta (LT-β) to help kill chronically infected macrophages that can no longer kill pathogens. The killing of chronically infected macrophages release pathogens to the extracellular space that can then be killed by other activated macrophages. T H 1 cells also help recruit more monocytes, the precursor to macrophages, to the infection site. T H 1 secretion TNF-α and LT-α to make blood vessels easier for monocytes to bind to and exit. T H 1 secretion of CCL2 as a chemoattractant for monocytes. IL-3 and GM-CSF released by T H 1 cells stimulate more monocyte production in the bone marrow. When intracellular pathogens cannot be eliminated, such as in the case of Mycobacterium tuberculosis , the pathogen is contained through the formation of granuloma , an aggregation of infected macrophages surrounded by activated T cells. The macrophages bordering the activated lymphocytes often fuse to form multinucleated giant cells that appear to have increased antimicrobial ability due to their proximity to T H 1 cells, but over time, the cells in the center start to die and form necrotic tissue. T H 2 cells play an important role in alternative macrophage activation as part of type 2 immune response against large extracellular pathogens like helminths . T H 2 cells secrete IL-4 and IL-13, which activate macrophages to become M2 macrophages, also known as alternatively activated macrophages. M2 macrophages express arginase-1 , an enzyme that converts arginine to ornithine and urea . Ornithine help increase smooth muscle contraction to expel the worm and also participates in tissue and wound repair. Ornithine can be further metabolized to proline , which is essential for synthesizing collagen . M2 macrophages can also decrease inflammation by producing IL-1 receptor antagonist (IL-1RA) and IL-1 receptors that do not lead to downstream inflammatory signaling (IL-1RII). Another part of the adaptive immunity activation involves stimulating CD8 + via cross presentation of antigens peptides on MHC class I molecules. Studies have shown that proinflammatory macrophages are capable of cross presentation of antigens on MHC class I molecules, but whether macrophage cross-presentation plays a role in naïve or memory CD8 + T cell activation is still unclear. Macrophages have been shown to secrete cytokines BAFF and APRIL, which are important for plasma cell isotype switching. APRIL and IL-6 secreted by macrophage precursors in the bone marrow help maintain survival of plasma cells homed to the bone marrow. There are several activated forms of macrophages. In spite of a spectrum of ways to activate macrophages, there are two main groups designated M1 and M2 . M1 macrophages: as mentioned earlier (previously referred to as classically activated macrophages), M1 "killer" macrophages are activated by LPS and IFN-gamma , and secrete high levels of IL-12 and low levels of IL-10 . M1 macrophages have pro-inflammatory, bactericidal, and phagocytic functions. In contrast, the M2 "repair" designation (also referred to as alternatively activated macrophages) broadly refers to macrophages that function in constructive processes like wound healing and tissue repair, and those that turn off damaging immune system activation by producing anti-inflammatory cytokines like IL-10 . M2 is the phenotype of resident tissue macrophages, and can be further elevated by IL-4 . M2 macrophages produce high levels of IL-10, TGF-beta and low levels of IL-12. Tumor-associated macrophages are mainly of the M2 phenotype, and seem to actively promote tumor growth. Macrophages exist in a variety of phenotypes which are determined by the role they play in wound maturation. Phenotypes can be predominantly separated into two major categories; M1 and M2. M1 macrophages are the dominating phenotype observed in the early stages of inflammation and are activated by four key mediators: interferon-γ (IFN-γ), tumor necrosis factor (TNF), and damage associated molecular patterns (DAMPs). These mediator molecules create a pro-inflammatory response that in return produce pro-inflammatory cytokines like Interleukin-6 and TNF. Unlike M1 macrophages, M2 macrophages secrete an anti-inflammatory response via the addition of Interleukin-4 or Interleukin-13. They also play a role in wound healing and are needed for revascularization and reepithelialization. M2 macrophages are divided into four major types based on their roles: M2a, M2b, M2c, and M2d. How M2 phenotypes are determined is still up for discussion but studies have shown that their environment allows them to adjust to whichever phenotype is most appropriate to efficiently heal the wound. M2 macrophages are needed for vascular stability. They produce vascular endothelial growth factor-A and TGF-β1 . There is a phenotype shift from M1 to M2 macrophages in acute wounds, however this shift is impaired for chronic wounds. This dysregulation results in insufficient M2 macrophages and its corresponding growth factors that aid in wound repair. With a lack of these growth factors/anti-inflammatory cytokines and an overabundance of pro-inflammatory cytokines from M1 macrophages chronic wounds are unable to heal in a timely manner. Normally, after neutrophils eat debris/pathogens they perform apoptosis and are removed. At this point, inflammation is not needed and M1 undergoes a switch to M2 (anti-inflammatory). However, dysregulation occurs as the M1 macrophages are unable/do not phagocytose neutrophils that have undergone apoptosis leading to increased macrophage migration and inflammation. Both M1 and M2 macrophages play a role in promotion of atherosclerosis . M1 macrophages promote atherosclerosis by inflammation. M2 macrophages can remove cholesterol from blood vessels, but when the cholesterol is oxidized, the M2 macrophages become apoptotic foam cells contributing to the atheromatous plaque of atherosclerosis. The first step to understanding the importance of macrophages in muscle repair, growth, and regeneration is that there are two "waves" of macrophages with the onset of damageable muscle use– subpopulations that do and do not directly have an influence on repairing muscle. The initial wave is a phagocytic population that comes along during periods of increased muscle use that are sufficient to cause muscle membrane lysis and membrane inflammation, which can enter and degrade the contents of injured muscle fibers. These early-invading, phagocytic macrophages reach their highest concentration about 24 hours following the onset of some form of muscle cell injury or reloading. Their concentration rapidly declines after 48 hours. The second group is the non-phagocytic types that are distributed near regenerative fibers. These peak between two and four days and remain elevated for several days during while muscle tissue is rebuilding. The first subpopulation has no direct benefit to repairing muscle, while the second non-phagocytic group does. It is thought that macrophages release soluble substances that influence the proliferation, differentiation, growth, repair, and regeneration of muscle, but at this time the factor that is produced to mediate these effects is unknown. It is known that macrophages' involvement in promoting tissue repair is not muscle specific; they accumulate in numerous tissues during the healing process phase following injury. Macrophages are essential for wound healing . They replace polymorphonuclear neutrophils as the predominant cells in the wound by day two after injury. Attracted to the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enter the area through blood vessel walls. Numbers of monocytes in the wound peak one to one and a half days after the injury occurs. Once they are in the wound site, monocytes mature into macrophages. The spleen contains half the body's monocytes in reserve ready to be deployed to injured tissue. The macrophage's main role is to phagocytize bacteria and damaged tissue, and they also debride damaged tissue by releasing proteases. Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wound days. These factors attract cells involved in the proliferation stage of healing to the area. Macrophages may also restrain the contraction phase. Macrophages are stimulated by the low oxygen content of their surroundings to produce factors that induce and speed angiogenesis and they also stimulate cells that re-epithelialize the wound, create granulation tissue, and lay down a new extracellular matrix . [ better source needed ] By secreting these factors, macrophages contribute to pushing the wound healing process into the next phase.Scientists have elucidated that as well as eating up material debris, macrophages are involved in the typical limb regeneration in the salamander. They found that removing the macrophages from a salamander resulted in failure of limb regeneration and a scarring response. As described above, macrophages play a key role in removing dying or dead cells and cellular debris. Erythrocytes have a lifespan on average of 120 days and so are constantly being destroyed by macrophages in the spleen and liver. Macrophages will also engulf macromolecules , and so play a key role in the pharmacokinetics of parenteral irons . [ citation needed ] The iron that is released from the haemoglobin is either stored internally in ferritin or is released into the circulation via ferroportin . In cases where systemic iron levels are raised, or where inflammation is present, raised levels of hepcidin act on macrophage ferroportin channels, leading to iron remaining within the macrophages. [ citation needed ]Melanophages are a subset of tissue-resident macrophages able to absorb pigment, either native to the organism or exogenous (such as tattoos ), from extracellular space. In contrast to dendritic juncional melanocytes , which synthesize melanosomes and contain various stages of their development, the melanophages only accumulate phagocytosed melanin in lysosome-like phagosomes. This occurs repeatedly as the pigment from dead dermal macrophages is phagocytosed by their successors, preserving the tattoo in the same place. Every tissue harbors its own specialized population of resident macrophages, which entertain reciprocal interconnections with the stroma and functional tissue. These resident macrophages are sessile (non-migratory), provide essential growth factors to support the physiological function of the tissue (e.g. macrophage-neuronal crosstalk in the guts), and can actively protect the tissue from inflammatory damage. Nerve-associated macrophages or NAMs are those tissue-resident macrophages that are associated with nerves. Some of them are known to have an elongated morphology of up to 200μm Due to their role in phagocytosis, macrophages are involved in many diseases of the immune system. For example, they participate in the formation of granulomas , inflammatory lesions that may be caused by a large number of diseases. Some disorders, mostly rare, of ineffective phagocytosis and macrophage function have been described, for example. In their role as a phagocytic immune cell macrophages are responsible for engulfing pathogens to destroy them. Some pathogens subvert this process and instead live inside the macrophage. This provides an environment in which the pathogen is hidden from the immune system and allows it to replicate. [ citation needed ] Diseases with this type of behaviour include tuberculosis (caused by Mycobacterium tuberculosis ) and leishmaniasis (caused by Leishmania species). [ citation needed ] In order to minimize the possibility of becoming the host of an intracellular bacteria, macrophages have evolved defense mechanisms such as induction of nitric oxide and reactive oxygen intermediates, which are toxic to microbes. Macrophages have also evolved the ability to restrict the microbe's nutrient supply and induce autophagy . Once engulfed by a macrophage, the causative agent of tuberculosis, Mycobacterium tuberculosis , avoids cellular defenses and uses the cell to replicate. Recent evidence suggests that in response to the pulmonary infection of Mycobacterium tuberculosis , the peripheral macrophages matures into M1 phenotype. Macrophage M1 phenotype is characterized by increased secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and increased glycolytic activities essential for clearance of infection. Upon phagocytosis by a macrophage, the Leishmania parasite finds itself in a phagocytic vacuole. Under normal circumstances, this phagocytic vacuole would develop into a lysosome and its contents would be digested. Leishmania alter this process and avoid being destroyed; instead, they make a home inside the vacuole. [ citation needed ] Infection of macrophages in joints is associated with local inflammation during and after the acute phase of Chikungunya (caused by CHIKV or Chikungunya virus). Adenovirus (most common cause of pink eye) can remain latent in a host macrophage, with continued viral shedding 6–18 months after initial infection. [ citation needed ] Brucella spp. can remain latent in a macrophage via inhibition of phagosome – lysosome fusion; causes brucellosis (undulant fever). [ citation needed ] Legionella pneumophila , the causative agent of Legionnaires' disease , also establishes residence within macrophages. [ citation needed ] Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis . Focal recruitment of macrophages occurs after the onset of acute myocardial infarction . These macrophages function to remove debris, apoptotic cells and to prepare for tissue regeneration . Macrophages protect against ischemia-induced ventricular tachycardia in hypokalemic mice. Macrophages also play a role in human immunodeficiency virus (HIV) infection. Like T cells , macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body. HIV can enter the macrophage through binding of gp120 to CD4 and second membrane receptor, CCR5 (a chemokine receptor). Both circulating monocytes and macrophages serve as a reservoir for the virus. Macrophages are better able to resist infection by HIV-1 than CD4+ T cells, although susceptibility to HIV infection differs among macrophage subtypes. Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells. Inflammatory compounds, such as tumor necrosis factor (TNF)-alpha released by the macrophages activate the gene switch nuclear factor-kappa B . NF-κB then enters the nucleus of a tumor cell and turns on production of proteins that stop apoptosis and promote cell proliferation and inflammation. Moreover, macrophages serve as a source for many pro-angiogenic factors including vascular endothelial factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor (M-CSF/CSF1) and IL-1 and IL-6 , contributing further to the tumor growth. Macrophages have been shown to infiltrate a number of tumors. Their number correlates with poor prognosis in certain cancers, including cancers of breast, cervix, bladder, brain and prostate. Some tumors can also produce factors, including M-CSF/CSF1, MCP-1/CCL2 and Angiotensin II , that trigger the amplification and mobilization of macrophages in tumors. Additionally, subcapsular sinus macrophages in tumor-draining lymph nodes can suppress cancer progression by containing the spread of tumor-derived materials. Experimental studies indicate that macrophages can affect all therapeutic modalities, including surgery , chemotherapy , radiotherapy , immunotherapy and targeted therapy . Macrophages can influence treatment outcomes both positively and negatively. Macrophages can be protective in different ways: they can remove dead tumor cells (in a process called phagocytosis ) following treatments that kill these cells; they can serve as drug depots for some anticancer drugs; they can also be activated by some therapies to promote antitumor immunity. Macrophages can also be deleterious in several ways: for example they can suppress various chemotherapies, radiotherapies and immunotherapies. Because macrophages can regulate tumor progression, therapeutic strategies to reduce the number of these cells, or to manipulate their phenotypes, are currently being tested in cancer patients. However, macrophages are also involved in antibody mediated cytotoxicity (ADCC) and this mechanism has been proposed to be important for certain cancer immunotherapy antibodies. It has been observed that increased number of pro-inflammatory macrophages within obese adipose tissue contributes to obesity complications including insulin resistance and diabetes type 2. The modulation of the inflammatory state of adipose tissue macrophages has therefore been considered a possible therapeutic target to treat obesity-related diseases. Although adipose tissue macrophages are subject to anti-inflammatory homeostatic control by sympathetic innervation, experiments using ADRB2 gene knockout mice indicate that this effect is indirectly exerted through the modulation of adipocyte function, and not through direct Beta-2 adrenergic receptor activation, suggesting that adrenergic stimulation of macrophages may be insufficient to impact adipose tissue inflammation or function in obesity. Within the fat ( adipose ) tissue of CCR2 deficient mice , there is an increased number of eosinophils , greater alternative macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet. This is partially caused by a phenotype switch of macrophages induced by necrosis of fat cells ( adipocytes ). In an obese individual some adipocytes burst and undergo necrotic death, which causes the residential M2 macrophages to switch to M1 phenotype. This is one of the causes of a low-grade systemic chronic inflammatory state associated with obesity. In their role as a phagocytic immune cell macrophages are responsible for engulfing pathogens to destroy them. Some pathogens subvert this process and instead live inside the macrophage. This provides an environment in which the pathogen is hidden from the immune system and allows it to replicate. [ citation needed ] Diseases with this type of behaviour include tuberculosis (caused by Mycobacterium tuberculosis ) and leishmaniasis (caused by Leishmania species). [ citation needed ] In order to minimize the possibility of becoming the host of an intracellular bacteria, macrophages have evolved defense mechanisms such as induction of nitric oxide and reactive oxygen intermediates, which are toxic to microbes. Macrophages have also evolved the ability to restrict the microbe's nutrient supply and induce autophagy . Once engulfed by a macrophage, the causative agent of tuberculosis, Mycobacterium tuberculosis , avoids cellular defenses and uses the cell to replicate. Recent evidence suggests that in response to the pulmonary infection of Mycobacterium tuberculosis , the peripheral macrophages matures into M1 phenotype. Macrophage M1 phenotype is characterized by increased secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and increased glycolytic activities essential for clearance of infection. Upon phagocytosis by a macrophage, the Leishmania parasite finds itself in a phagocytic vacuole. Under normal circumstances, this phagocytic vacuole would develop into a lysosome and its contents would be digested. Leishmania alter this process and avoid being destroyed; instead, they make a home inside the vacuole. [ citation needed ] Infection of macrophages in joints is associated with local inflammation during and after the acute phase of Chikungunya (caused by CHIKV or Chikungunya virus). Adenovirus (most common cause of pink eye) can remain latent in a host macrophage, with continued viral shedding 6–18 months after initial infection. [ citation needed ] Brucella spp. can remain latent in a macrophage via inhibition of phagosome – lysosome fusion; causes brucellosis (undulant fever). [ citation needed ] Legionella pneumophila , the causative agent of Legionnaires' disease , also establishes residence within macrophages. [ citation needed ]Once engulfed by a macrophage, the causative agent of tuberculosis, Mycobacterium tuberculosis , avoids cellular defenses and uses the cell to replicate. Recent evidence suggests that in response to the pulmonary infection of Mycobacterium tuberculosis , the peripheral macrophages matures into M1 phenotype. Macrophage M1 phenotype is characterized by increased secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and increased glycolytic activities essential for clearance of infection. Upon phagocytosis by a macrophage, the Leishmania parasite finds itself in a phagocytic vacuole. Under normal circumstances, this phagocytic vacuole would develop into a lysosome and its contents would be digested. Leishmania alter this process and avoid being destroyed; instead, they make a home inside the vacuole. [ citation needed ]Infection of macrophages in joints is associated with local inflammation during and after the acute phase of Chikungunya (caused by CHIKV or Chikungunya virus). Adenovirus (most common cause of pink eye) can remain latent in a host macrophage, with continued viral shedding 6–18 months after initial infection. [ citation needed ] Brucella spp. can remain latent in a macrophage via inhibition of phagosome – lysosome fusion; causes brucellosis (undulant fever). [ citation needed ] Legionella pneumophila , the causative agent of Legionnaires' disease , also establishes residence within macrophages. [ citation needed ]Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis . Focal recruitment of macrophages occurs after the onset of acute myocardial infarction . These macrophages function to remove debris, apoptotic cells and to prepare for tissue regeneration . Macrophages protect against ischemia-induced ventricular tachycardia in hypokalemic mice. Macrophages also play a role in human immunodeficiency virus (HIV) infection. Like T cells , macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body. HIV can enter the macrophage through binding of gp120 to CD4 and second membrane receptor, CCR5 (a chemokine receptor). Both circulating monocytes and macrophages serve as a reservoir for the virus. Macrophages are better able to resist infection by HIV-1 than CD4+ T cells, although susceptibility to HIV infection differs among macrophage subtypes. Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells. Inflammatory compounds, such as tumor necrosis factor (TNF)-alpha released by the macrophages activate the gene switch nuclear factor-kappa B . NF-κB then enters the nucleus of a tumor cell and turns on production of proteins that stop apoptosis and promote cell proliferation and inflammation. Moreover, macrophages serve as a source for many pro-angiogenic factors including vascular endothelial factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor (M-CSF/CSF1) and IL-1 and IL-6 , contributing further to the tumor growth. Macrophages have been shown to infiltrate a number of tumors. Their number correlates with poor prognosis in certain cancers, including cancers of breast, cervix, bladder, brain and prostate. Some tumors can also produce factors, including M-CSF/CSF1, MCP-1/CCL2 and Angiotensin II , that trigger the amplification and mobilization of macrophages in tumors. Additionally, subcapsular sinus macrophages in tumor-draining lymph nodes can suppress cancer progression by containing the spread of tumor-derived materials. Experimental studies indicate that macrophages can affect all therapeutic modalities, including surgery , chemotherapy , radiotherapy , immunotherapy and targeted therapy . Macrophages can influence treatment outcomes both positively and negatively. Macrophages can be protective in different ways: they can remove dead tumor cells (in a process called phagocytosis ) following treatments that kill these cells; they can serve as drug depots for some anticancer drugs; they can also be activated by some therapies to promote antitumor immunity. Macrophages can also be deleterious in several ways: for example they can suppress various chemotherapies, radiotherapies and immunotherapies. Because macrophages can regulate tumor progression, therapeutic strategies to reduce the number of these cells, or to manipulate their phenotypes, are currently being tested in cancer patients. However, macrophages are also involved in antibody mediated cytotoxicity (ADCC) and this mechanism has been proposed to be important for certain cancer immunotherapy antibodies. It has been observed that increased number of pro-inflammatory macrophages within obese adipose tissue contributes to obesity complications including insulin resistance and diabetes type 2. The modulation of the inflammatory state of adipose tissue macrophages has therefore been considered a possible therapeutic target to treat obesity-related diseases. Although adipose tissue macrophages are subject to anti-inflammatory homeostatic control by sympathetic innervation, experiments using ADRB2 gene knockout mice indicate that this effect is indirectly exerted through the modulation of adipocyte function, and not through direct Beta-2 adrenergic receptor activation, suggesting that adrenergic stimulation of macrophages may be insufficient to impact adipose tissue inflammation or function in obesity. Within the fat ( adipose ) tissue of CCR2 deficient mice , there is an increased number of eosinophils , greater alternative macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet. This is partially caused by a phenotype switch of macrophages induced by necrosis of fat cells ( adipocytes ). In an obese individual some adipocytes burst and undergo necrotic death, which causes the residential M2 macrophages to switch to M1 phenotype. This is one of the causes of a low-grade systemic chronic inflammatory state associated with obesity. Though very similar in structure to tissue macrophages, intestinal macrophages have evolved specific characteristics and functions given their natural environment, which is in the digestive tract. Macrophages and intestinal macrophages have high plasticity causing their phenotype to be altered by their environments. Like macrophages, intestinal macrophages are differentiated monocytes, though intestinal macrophages have to coexist with the microbiome in the intestines. This is a challenge considering the bacteria found in the gut are not recognized as "self" and could be potential targets for phagocytosis by the macrophage. To prevent the destruction of the gut bacteria, intestinal macrophages have developed key differences compared to other macrophages. Primarily, intestinal macrophages do not induce inflammatory responses. Whereas tissue macrophages release various inflammatory cytokines, such as IL-1, IL-6 and TNF-α, intestinal macrophages do not produce or secrete inflammatory cytokines. This change is directly caused by the intestinal macrophages environment. Surrounding intestinal epithelial cells release TGF-β , which induces the change from proinflammatory macrophage to noninflammatory macrophage. Even though the inflammatory response is downregulated in intestinal macrophages, phagocytosis is still carried out. There is no drop off in phagocytosis efficiency as intestinal macrophages are able to effectively phagocytize the bacteria, S. typhimurium and E. coli , but intestinal macrophages still do not release cytokines, even after phagocytosis. Also, intestinal macrophages do not express lipopolysaccharide (LPS), IgA, or IgG receptors. The lack of LPS receptors is important for the gut as the intestinal macrophages do not detect the microbe-associated molecular patterns (MAMPS/PAMPS) of the intestinal microbiome. Nor do they express IL-2 and IL-3 growth factor receptors. Intestinal macrophages have been shown to play a role in inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC). In a healthy gut, intestinal macrophages limit the inflammatory response in the gut, but in a disease-state, intestinal macrophage numbers and diversity are altered. This leads to inflammation of the gut and disease symptoms of IBD. Intestinal macrophages are critical in maintaining gut homeostasis . The presence of inflammation or pathogen alters this homeostasis, and concurrently alters the intestinal macrophages. There has yet to be a determined mechanism for the alteration of the intestinal macrophages by recruitment of new monocytes or changes in the already present intestinal macrophages. Additionally, a new study reveals macrophages limit iron access to bacteria by releasing extracellular vesicles, improving sepsis outcomes. Intestinal macrophages have been shown to play a role in inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC). In a healthy gut, intestinal macrophages limit the inflammatory response in the gut, but in a disease-state, intestinal macrophage numbers and diversity are altered. This leads to inflammation of the gut and disease symptoms of IBD. Intestinal macrophages are critical in maintaining gut homeostasis . The presence of inflammation or pathogen alters this homeostasis, and concurrently alters the intestinal macrophages. There has yet to be a determined mechanism for the alteration of the intestinal macrophages by recruitment of new monocytes or changes in the already present intestinal macrophages. Additionally, a new study reveals macrophages limit iron access to bacteria by releasing extracellular vesicles, improving sepsis outcomes. Macrophages were first discovered late in the 19th century by Élie Metchnikoff . Élie Metchnikoff revolutionized the branch of macrophages by combining philosophical insights and the evolutionary study of life. Later on, Van Furth during the 1960s proposed the idea that circulating blood monocytes in adults allowed for the origin of all tissue macrophages. In recent years, publishing regarding macrophages has led people to believe that multiple resident tissue macrophages are independent of the blood monocytes as it is formed during the embryonic stage of development. Within the 21st century, all the ideas concerning the origin of macrophages (present in tissues) are compiled together to suggest that physiologically complex organisms, form macrophages independently by mechanisms that don't have to depend on the blood monocytes.

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Chikungunya

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Neglected tropical diseases

Neglected tropical diseases ( NTDs ) are a diverse group of tropical infections that are common in low-income populations in developing regions of Africa , Asia , and the Americas . They are caused by a variety of pathogens , such as viruses , bacteria , protozoa , and parasitic worms ( helminths ). These diseases are contrasted with the "big three" infectious diseases ( HIV/AIDS , tuberculosis , and malaria ), which generally receive greater treatment and research funding. In sub-Saharan Africa, the effect of neglected tropical diseases as a group is comparable to that of malaria and tuberculosis. NTD co-infection can also make HIV/AIDS and tuberculosis more deadly. Some treatments for NTDs are relatively inexpensive. For example, treatment for schistosomiasis costs US$0.20 per child per year. Nevertheless, in 2010 it was estimated that control of neglected diseases would require funding of between US$2 billion and $3 billion over the subsequent five to seven years. Some pharmaceutical companies have committed to donating all the drug therapies required, and mass drug administration efforts (for example, mass deworming ) have been successful in several countries. While preventive measures are often more accessible in the developed world , they are not universally available in poorer areas. Within developed countries, neglected tropical diseases affect the very poorest in society. In the United States, there are up to 1.46 million families, including 2.8 million children, living on less than two dollars per day. In developed countries, the burdens of neglected tropical diseases are often overshadowed by other public health issues. However, many of the same issues put populations at risk in developed as well as developing nations. For example, other problems stemming from poverty, such as lack of adequate housing , can expose individuals to the vectors of these diseases. Twenty neglected tropical diseases are prioritized by the World Health Organization (WHO), though other organizations define NTDs differently. Chromoblastomycosis and other deep mycoses , scabies and other ectoparasites , and snakebite envenomation were added to the WHO list in 2017. These diseases are common in 149 countries, affecting more than 1.4 billion people (including more than 500 million children) and costing developing economies billions of dollars every year. They resulted in 142,000 deaths in 2013, down from 204,000 deaths in 1990. The importance of neglected tropical diseases has been underestimated since many are asymptomatic and have long incubation periods . The connection between death and a neglected tropical disease that has been latent for a long period is often not realized. Areas of high endemicity are often geographically isolated, making treatment and prevention much more difficult. There are three other major reasons that these diseases have been overlooked: they mainly affect the poorest countries of the developing world ; in recent years public health efforts have focused heavily on decreasing the prevalence of HIV/AIDS, tuberculosis, and malaria (far more resources are given to those three diseases because of their higher mortality rates and higher public awareness of them); and neglected tropical diseases do not currently have a prominent cultural figure to champion their elimination. Neglected tropical diseases are often associated with social stigma , making their treatment more complex. Public health research has only recently begun to focus on stigma as a component of the issue. From the 1960s onward, approximately one citation a year related to social stigma. In 2006, there were 458. Stigma greatly affects disease control by decreasing help-seeking and treatment adherence. Disease control programs since the 1980s, have begun to integrate stigma mitigation into their offerings. In India , a leprosy program prioritized the message that "leprosy is curable, not hereditary" in order to inspire optimism in highly affected communities. The goal was to make leprosy a disease "like any other", so as to reduce stigma. At the same time, medical resources were optimized to fulfill the promise that the disease could be cured. Treatment and prevention of neglected tropical diseases are not seen as profitable, so patents and profit play no role in stimulating innovation. Like all non-commercial areas, these communities affected by these diseases are reliant on governments and philanthropy (including industry philanthropy). Currently, the pharmaceutical industry views research and development as highly risky. For this reason, resources are not often put into the field of NTDs, and new chemical products are often expensive. A review of public and private initiatives found that of the 1,393 new chemical products that were marketed between 1975 and 1999, only 16 were related to tropical diseases and tuberculosis. The same review found that there was a 13-fold greater chance of a newly marketed drug being for central nervous system disorders or cancer than for an NTD. Because of a lack of economic incentives for the pharmaceutical industry, successful NTD treatment programs have often relied on donations. The Mectizan Donation Program has donated over 1.8 billion tablets of ivermectin . While developed countries often rely on government-run and private partnerships to fund such projects, developing nations frequently have significantly lower per-person spending on these diseases. A 2006 report found that the Gates Foundation funded most extra activities to counter these diseases. Since 2008, the concept of "neglected diseases of poverty" has been developed and explored. This group of diseases, which overlaps with neglected tropical diseases, also pose a threat to human health in developed nations. In the United States alone, there are at least 12 million people with neglected parasitic infections. They make up a hidden disease burden among the poorest people in wealthy societies . In developed nations, lack of knowledge in the healthcare industry and lack of conclusive diagnostic tests perpetuate the neglect of this group of diseases. In the United States, high rates of parasitic infection can be distributed along geographic, racial, and socio-economic lines. Among African Americans , there may be up to 2.8 million cases of toxocariasis . Toxocariasis, trichomoniasis , and some other neglected infections occur in the United States at the same rate as in Nigeria . Within the Hispanic community, neglected infections are concentrated near the US–Mexico border . Vector-borne illnesses are especially high, with some rates approaching those of Latin America . Chagas disease was found in the US as early as the 1970s. However, in the developed world, diseases that are associated with poverty are often not addressed comprehensively. This may be due to a lack of economic incentives and public policy failings. A lack of awareness prevents effective policy generation and leaves healthcare services unequipped to address the issue. Additionally, little effort is put into creating and maintaining large data sets on neglected diseases in the United States and other developed nations. The first summit on the issue was held by the Adler Institute on Social Exclusion in the United States in 2009. In Europe , a similar trend is seen. Neglected tropical diseases are concentrated in eastern and southern Europe , where poverty levels are highest. The most prevalent diseases in this region are ascariasis , trichuriasis , zoonotic helminth infections , and visceral leishmaniasis . Migration paths to Europe, most notably to Spain , have brought diseases to Europe as well. As many as 6,000 cases of Chagas disease have been introduced in this way. In response to a growing awareness of the burden on these populations, the European Centre for Disease Prevention and Control has laid out ten public health guidelines. They cover a variety of topics, from health education and promotion to community partnerships and the development of a minority healthcare workforce. Neglected tropical diseases are often associated with social stigma , making their treatment more complex. Public health research has only recently begun to focus on stigma as a component of the issue. From the 1960s onward, approximately one citation a year related to social stigma. In 2006, there were 458. Stigma greatly affects disease control by decreasing help-seeking and treatment adherence. Disease control programs since the 1980s, have begun to integrate stigma mitigation into their offerings. In India , a leprosy program prioritized the message that "leprosy is curable, not hereditary" in order to inspire optimism in highly affected communities. The goal was to make leprosy a disease "like any other", so as to reduce stigma. At the same time, medical resources were optimized to fulfill the promise that the disease could be cured. Treatment and prevention of neglected tropical diseases are not seen as profitable, so patents and profit play no role in stimulating innovation. Like all non-commercial areas, these communities affected by these diseases are reliant on governments and philanthropy (including industry philanthropy). Currently, the pharmaceutical industry views research and development as highly risky. For this reason, resources are not often put into the field of NTDs, and new chemical products are often expensive. A review of public and private initiatives found that of the 1,393 new chemical products that were marketed between 1975 and 1999, only 16 were related to tropical diseases and tuberculosis. The same review found that there was a 13-fold greater chance of a newly marketed drug being for central nervous system disorders or cancer than for an NTD. Because of a lack of economic incentives for the pharmaceutical industry, successful NTD treatment programs have often relied on donations. The Mectizan Donation Program has donated over 1.8 billion tablets of ivermectin . While developed countries often rely on government-run and private partnerships to fund such projects, developing nations frequently have significantly lower per-person spending on these diseases. A 2006 report found that the Gates Foundation funded most extra activities to counter these diseases. Since 2008, the concept of "neglected diseases of poverty" has been developed and explored. This group of diseases, which overlaps with neglected tropical diseases, also pose a threat to human health in developed nations. In the United States alone, there are at least 12 million people with neglected parasitic infections. They make up a hidden disease burden among the poorest people in wealthy societies . In developed nations, lack of knowledge in the healthcare industry and lack of conclusive diagnostic tests perpetuate the neglect of this group of diseases. In the United States, high rates of parasitic infection can be distributed along geographic, racial, and socio-economic lines. Among African Americans , there may be up to 2.8 million cases of toxocariasis . Toxocariasis, trichomoniasis , and some other neglected infections occur in the United States at the same rate as in Nigeria . Within the Hispanic community, neglected infections are concentrated near the US–Mexico border . Vector-borne illnesses are especially high, with some rates approaching those of Latin America . Chagas disease was found in the US as early as the 1970s. However, in the developed world, diseases that are associated with poverty are often not addressed comprehensively. This may be due to a lack of economic incentives and public policy failings. A lack of awareness prevents effective policy generation and leaves healthcare services unequipped to address the issue. Additionally, little effort is put into creating and maintaining large data sets on neglected diseases in the United States and other developed nations. The first summit on the issue was held by the Adler Institute on Social Exclusion in the United States in 2009. In Europe , a similar trend is seen. Neglected tropical diseases are concentrated in eastern and southern Europe , where poverty levels are highest. The most prevalent diseases in this region are ascariasis , trichuriasis , zoonotic helminth infections , and visceral leishmaniasis . Migration paths to Europe, most notably to Spain , have brought diseases to Europe as well. As many as 6,000 cases of Chagas disease have been introduced in this way. In response to a growing awareness of the burden on these populations, the European Centre for Disease Prevention and Control has laid out ten public health guidelines. They cover a variety of topics, from health education and promotion to community partnerships and the development of a minority healthcare workforce. There is some debate among the WHO, CDC , and infectious disease experts over which diseases are classified as neglected tropical diseases. Feasey, a researcher in neglected tropical diseases, notes 13 neglected tropical diseases: ascariasis , Buruli ulcer , Chagas disease , dracunculiasis , hookworm infection, human African trypanosomiasis , leishmaniasis , leprosy , lymphatic filariasis , onchocerciasis , schistosomiasis , trachoma , and trichuriasis . Fenwick recognizes 12 "core" neglected tropical diseases: the same as above, excluding hookworm. These diseases result from four classes of causative pathogens : (i) protozoa (Chagas disease, human African trypanosomiasis, and leishmaniasis); (ii) bacteria (Buruli ulcer, leprosy, trachoma, and yaws ), (iii) helminths or metazoan worms ( cysticercosis / taeniasis , dracunculiasis, echinococcosis , foodborne trematodiases , lymphatic filariasis, onchocerciasis, schistosomiasis, and soil-transmitted helminthiasis ); and (iv) viruses ( dengue , chikungunya , and rabies ). [ citation needed ] The WHO recognizes the twenty diseases below as neglected tropical diseases. Helminth infections: Viral infections: Bacterial infections: Fungal infections: Ectoparasites: Non-infectious diseases caused by toxin exposure: The World Health Organization's 2010 report on neglected tropical diseases offers an expanded list including dengue, rabies, yaws, cysticercosis, echinococcosis, and foodborne trematode infections . Buruli ulcer is caused by the bacterium Mycobacterium ulcerans . It is related to the bacteria that cause tuberculosis and leprosy. Mycobacterium ulcerans produces a toxin, mycolactone , that destroys tissue. The prevalence of Buruli ulcer is unknown. The risk of mortality is low, although secondary infections can be lethal. Morbidity takes the form of deformity, disability, and skin lesions, which can be prevented through early treatment with antibiotics and surgery. It is found in Africa, Asia, Australia, and Latin America. Chagas disease is also known as American trypanosomiasis. There are approximately 15 million people infected with Chagas disease. Morbidity rates are higher for immunocompromised individuals, children, and the elderly, but can be very low if the disease is treated early. Chagas disease does not kill victims rapidly, instead causing years of debilitating chronic symptoms. It is caused by the vector-borne protozoa Trypanosoma cruzi . It is spread by contact with Trypanosoma cruzi -infected feces of the triatomine ( assassin bug ). The protozoan can enter the body via the bug's bite, skin breaks, or mucous membranes . Infection can result from eating infected food or coming into contact with contaminated bodily fluids. There are two phases of Chagas disease. The acute phase is usually asymptomatic. The first symptoms are usually skin chancres , unilateral purplish orbital oedema , local lymphadenopathy , and fever , accompanied by a variety of other symptoms depending on the infection site. The chronic phase occurs in 30 percent of all infections and can take three forms: asymptomatic (most prevalent), cardiac, and digestive lesions. Chagas disease can be prevented by avoiding insect bites through insecticide spraying, home improvement, bed nets, hygienic food, medical care, laboratory practices, and testing. It can be diagnosed through a serological test, although the test is not very accurate. Treatment is with medication, which may have severe side effects. There are 50–100 million dengue virus infections annually. Dengue fever is usually not fatal, but infection with one of four serotypes can increase later susceptibility to other serotypes, resulting in a potentially fatal disease called severe dengue. Dengue fever is caused by a flavivirus which is spread mostly by the bite of the Aedes aegypti mosquito. No treatment for either dengue or severe dengue exists beyond palliative care . The symptoms are high fever and flu-like symptoms. It is found in Asia, Latin America, and Northern Australia. Chikungunya is an arboviral disease transmitted by A. albopictus and A. aegypti mosquitoes. The virus was first isolated from an outbreak in Tanzania in 1952. Chikungunya virus is a member of the genus Alphavirus and family Togaviridae . The word "chikungunya" is from the Makonde language and means "that which bends up", referring to the effect of debilitating joint pain on the patient. Symptoms, generally appearing 5–7 days after exposure, can be confused with dengue and include fever, rash, headache, joint pain, and swelling. The disease mainly occurs in Africa and Asia. Dracunculiasis is also known as Guinea-worm disease. In 2019, 53 cases were reported across four countries, a substantial decrease from 3,500,000 cases in 1986. It is not fatal, but can cause months of inactivity. It is caused by drinking water contaminated by water fleas infected with guinea-worm larvae. Approximately one year after infection, a painful blister forms and one or more worms emerge. Worms can be up to 1 metre long. It is usually treated by World Health Organization volunteers who clean and bandage wounds caused by worms and return daily to pull the worm out a few more inches. Dracunculiasis is preventable by water filtration, immediate case identification to prevent spread, health education, and treating ponds with larvicide. An eradication program has been able to reduce prevalence. As of 2014 [ update ] , the four endemic countries are Chad , Ethiopia , Mali , and South Sudan . The rate of echinococcosis is higher in rural areas, and there are more than one million people infected currently. It is caused by ingesting parasites in animal feces. There are two versions of the disease: cystic and alveolar . Both versions involve an asymptomatic incubation period of several years. In the cystic version, liver cysts cause abdominal pain , nausea , and vomiting , while cysts in the lungs cause chronic cough , chest pain , and shortness of breath . In alveolar echinococcosis, a primary cyst develops, usually in the liver, in addition to weight loss, abdominal pain, malaise , and signs of liver failure . Untreated alveolar echinococcosis is fatal. Surgery and drugs can be used to treat echinococcosis. It can be prevented by deworming dogs, sanitation, proper disposal of animal feces, health education, and livestock vaccination. Cystic echinococcosis is found in the eastern portion of the Mediterranean region, northern Africa, southern and eastern Europe, the southern portion of South America, and Central Asia. Alveolar echinococcosis is found in western and northern China, Russia, Europe, and northern North America. It can be diagnosed through imaging techniques and serological tests . There are limited data available on the prevalence of yaws , although it primarily affects children. The mortality risk is very low, but the disease causes disfigurement and disability if untreated. The most common symptom is skin lesions. It is a chronic bacterial infection, transmitted by skin contact, and caused by the spirochete bacterium Treponema pallidum pertenue . It is treated with antibiotics and can be prevented through hygiene and sanitation. Yaws is most prevalent in warm, moist tropical regions of the Americas, Africa, Asia, and the Pacific. Foodborne trematode infections include clonorchiasis , opisthorchiasis , fascioliasis , and paragonimiasis . These infections are all zoonotic , primarily affecting domestic or wild animals, but can also be transmitted to humans. They are acquired by eating food, such as raw fish, contaminated with the larval stages of the parasites. At least 40 million people are thought to be infected. African trypanosomiasis (African sleeping sickness) is a somewhat rare protozoal disease, with fewer than 10,000 cases currently. Human African trypanosomiasis is vector-borne and spreads through the bite of the tsetse fly . The most common symptoms are fever, headache, lymphadenopathy , sleeping disturbances, personality changes, cognitive decline, and coma . The disease is always fatal if untreated. The current forms of treatment are highly toxic and ineffective, as resistance is spreading. It is diagnosed through an inexpensive serological test. [ medical citation needed ] The three forms of leishmaniasis , a protozoal disease, are visceral ( Kala-azar ), cutaneous , and mucocutaneous. There are an estimated 12 million people infected. It is fatal if untreated, and 20,000 deaths from visceral leishmaniasis occur annually. It is a vector-borne disease caused by the bite of sandflies . At least 90 percent of visceral leishmaniasis occurs in Bangladesh , Brazil , Ethiopia , India , South Sudan , and Sudan . Cutaneous leishmaniasis occurs in Afghanistan , Algeria , Brazil, Colombia , Iran , Pakistan , Peru , Saudi Arabia , and Syria . Around 90 percent of mucocutaneous leishmaniasis occurs in Bolivia , Brazil, and Peru. A vaccine is under development to prevent leishmaniasis. The only other method of prevention is avoidance of sandfly bites. Diagnosis can be made by clinical signs, serological tests, or parasitological tests. Leishmaniasis can be treated with expensive medications. According to recent figures from the WHO, 208,619 new cases of leprosy were reported in 2018 from 127 countries. It is most prevalent in India (69% of cases), Brazil, Indonesia , Nigeria , the Democratic Republic of the Congo , Madagascar , and East Africa from Mozambique to Ethiopia, with the highest relative incidence in India, Brazil, and Nepal . There are one to two million individuals currently disabled or disfigured due to past or present leprosy. It is caused by bacteria and transmitted through droplets from the mouth and nose of infected individuals. Leprosy causes disfigurement and physical disabilities if untreated. It is curable if treated early. Treatment requires multidrug therapy. The BCG vaccine has some preventative effect against leprosy. Leprosy has a 5–20 year incubation period, and the symptoms are damage to the skin, nerves, eyes, and limbs. Lymphatic filariasis is also known as elephantiasis . There are approximately 120 million individuals infected and 40 million with deformities. Approximately two-thirds of cases are in Southwest Asia, and one-third are in Africa. Lymphatic filariasis is rarely fatal but has lifelong implications, such as lymphoedema of the limbs, genital disease, and painful recurrent attacks. Most people are asymptomatic but have lymphatic damage. Up to 40 percent of infected individuals have kidney damage. It is a vector-borne disease, caused by nematode worms that are transmitted by mosquitoes. It can be treated with cost-effective antihelminthic treatments, and washing skin can slow or even reverse damage. It is diagnosed with a finger-prick blood test. Noma, an opportunistic bacterial infection causing gangrenous necrosis of the mouth, was added to the World Health Organization's list of neglected tropical diseases in December 2023. Onchocerciasis is also known as river blindness. There are 20.9 million people infected, and prevalence is higher in rural areas. Over 99 percent of cases are in sub-Saharan Africa . It causes blindness, skin rashes, lesions, intense itching, and skin depigmentation. It is a vector-borne disease, caused by blackflies infected with filarial worms. It can be treated with ivermectin and prevented by insecticide spraying or preventative dosing with ivermectin. There are two forms of rabies : furious and paralytic. It is mostly found in Asia and Africa. There is a higher prevalence in rural areas, and it disproportionately affects children. Rabies is fatal after symptoms develop. It is caused by a lyssavirus transmitted through wounds or bites from infected animals. The first symptoms are fever and pain near the infection site, which occur after a one- to three-month incubation period. Furious rabies (the more common type) causes hyperactivity, hydrophobia, and aerophobia; death by cardio-respiratory arrest occurs within days. Paralytic rabies causes a slow progression from paralysis to coma to death. There are 60,000 deaths from rabies annually. It can be prevented in dogs by vaccination and by cleaning and disinfecting bite wounds and post-exposure prophylaxis . Rabies is undiagnosable before symptoms develop. It can be detected through tissue testing after symptoms develop. There are over 200 million cases of schistosomiasis . Approximately 85 percent of cases are in sub-Saharan Africa. The disease can be fatal by causing bladder cancer and hematemesis . Schistosoma species have a complex life cycle that alternates between humans and freshwater snails. Infection occurs when the skin comes into contact with contaminated fresh water in which snails that carry the parasite are living. Symptoms for schistosomiasis are not caused by the worms but by the body's reaction to the eggs. The eggs that do not pass out of the body can become lodged in the intestine or bladder, causing inflammation or scarring. Children who are repeatedly infected can develop anemia, malnutrition, and learning difficulties. The symptoms are usually haematuria , bladder obstruction, renal failure , bladder cancer , periportal fibrosis, bladder fibrosis, liver fibrosis, portal hypertension , cervical lesions, ascites , and esophageal varices . Inexpensive praziquantel can be used to treat individuals with schistosomiasis, but it cannot prevent reinfection. The cost of prevention is US$0.32 per child per year. Mass deworming treatment with praziquantel, better access to safe water, sanitation, and health education can all be used to prevent schistosomiasis. Vaccines are under development. It can be diagnosed through a serological test, but the test often produces false negatives. Soil-transmitted helminthiasis is the most prevalent neglected tropical disease. The four major worm species responsible for soil-transmitted helminthiasis are Ascaris ( roundworms ), Trichuris ( whipworm ), the hookworms Necator americanus and Ancylostoma duodenale , and Strongyloides stercoralis . There are 1.5 billion people currently infected. Soil-transmitted helminthiasis occurs in sub-Saharan Africa, the Americas, China, and East Asia. The mortality risk is very low. The most common symptoms are anemia, stunted growth , intestinal problems, lack of energy, and compromised physical and cognitive development. Infected children often fall behind in schooling. The severity of symptoms depends on the number of worms in the body. Parasitic worms are generally transmitted via exposure to infected human feces and soil that are spread in the environment, for example, due to open defecation . The most common treatment is medicine. It can be prevented through hygienically prepared food and clean water, improved sanitation , periodic deworming, and health education. The World Health Organization recommends mass deworming without prior diagnosis. Cysticercosis is a tapeworm larvae infection, while taeniasis is infection with adult tapeworms . Both are found in Asia, Africa, and Latin America, particularly on farms in which pigs are exposed to human excrement. Cysticercosis is the most common preventable cause of epilepsy in the developing world. Cysticercosis occurs after ingestion of contaminated food, water, or soil. Cysts and lesions can cause headaches , blindness , seizures , hydrocephalus , meningitis , and dementia . Neurocysticercosis , or the parasitic infection of the nervous system, can be fatal. Taeniasis is not fatal. It is usually contracted after eating undercooked contaminated pork. Taeniasis has mild symptoms, including abdominal pain, nausea, diarrhea, or constipation. [ citation needed ] Drugs are used to treat both diseases. Infection can be prevented through stricter meat-inspection standards, livestock confinement, improved hygiene and sanitation, health education, safe meat preparation, and identifying and treating human and pig carriers. There are 21.4 million people infected with trachoma , of whom 2.2 million are partially blind and 1.2 million are blind. It is found in Africa, Asia, Central and South America, the Middle East, and Australia. The disease disproportionately affects women and children. The mortality risk is very low, although multiple re-infections eventually lead to blindness. The symptoms are internally scarred eyelids, followed by eyelids turning inward. Trachoma is caused by a micro-organism that spreads through eye discharges (on hands, cloth, etc.) and by "eye-seeking flies". It is treated with antibiotics. The only known prevention method is interpersonal hygiene. [ citation needed ] Chromoblastomycosis is a long-term fungal infection of the skin and subcutaneous tissue (a chronic subcutaneous mycosis ). It can be caused by many different types of fungi which become implanted under the skin , often by thorns or splinters. Chromoblastomycosis spreads very slowly. [ citation needed ] Other important endemic mycoses with common systemic involvement are histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, blastomycosis and talaromycosis. These infections are also seldomly seen in returning travelers in western countries Snakebite was added to the list in 2017, after years of criticism of the WHO by activists for not making it a priority. The greatest burden of snakebite morbidity is in India and Southeast Asia. Globally, there are an estimated 421,000 envenomings each year (about 1 in 4 snakebites) and 20,000 deaths, but snakebites often go unreported. A policy analysis however found that the placement of snakebite in the global health agenda of WHO is fragile due to reluctance acceptance of the disease in the neglected tropical disease community and the perceived colonial nature of the network driving the agenda. Buruli ulcer is caused by the bacterium Mycobacterium ulcerans . It is related to the bacteria that cause tuberculosis and leprosy. Mycobacterium ulcerans produces a toxin, mycolactone , that destroys tissue. The prevalence of Buruli ulcer is unknown. The risk of mortality is low, although secondary infections can be lethal. Morbidity takes the form of deformity, disability, and skin lesions, which can be prevented through early treatment with antibiotics and surgery. It is found in Africa, Asia, Australia, and Latin America. Chagas disease is also known as American trypanosomiasis. There are approximately 15 million people infected with Chagas disease. Morbidity rates are higher for immunocompromised individuals, children, and the elderly, but can be very low if the disease is treated early. Chagas disease does not kill victims rapidly, instead causing years of debilitating chronic symptoms. It is caused by the vector-borne protozoa Trypanosoma cruzi . It is spread by contact with Trypanosoma cruzi -infected feces of the triatomine ( assassin bug ). The protozoan can enter the body via the bug's bite, skin breaks, or mucous membranes . Infection can result from eating infected food or coming into contact with contaminated bodily fluids. There are two phases of Chagas disease. The acute phase is usually asymptomatic. The first symptoms are usually skin chancres , unilateral purplish orbital oedema , local lymphadenopathy , and fever , accompanied by a variety of other symptoms depending on the infection site. The chronic phase occurs in 30 percent of all infections and can take three forms: asymptomatic (most prevalent), cardiac, and digestive lesions. Chagas disease can be prevented by avoiding insect bites through insecticide spraying, home improvement, bed nets, hygienic food, medical care, laboratory practices, and testing. It can be diagnosed through a serological test, although the test is not very accurate. Treatment is with medication, which may have severe side effects. There are 50–100 million dengue virus infections annually. Dengue fever is usually not fatal, but infection with one of four serotypes can increase later susceptibility to other serotypes, resulting in a potentially fatal disease called severe dengue. Dengue fever is caused by a flavivirus which is spread mostly by the bite of the Aedes aegypti mosquito. No treatment for either dengue or severe dengue exists beyond palliative care . The symptoms are high fever and flu-like symptoms. It is found in Asia, Latin America, and Northern Australia. Chikungunya is an arboviral disease transmitted by A. albopictus and A. aegypti mosquitoes. The virus was first isolated from an outbreak in Tanzania in 1952. Chikungunya virus is a member of the genus Alphavirus and family Togaviridae . The word "chikungunya" is from the Makonde language and means "that which bends up", referring to the effect of debilitating joint pain on the patient. Symptoms, generally appearing 5–7 days after exposure, can be confused with dengue and include fever, rash, headache, joint pain, and swelling. The disease mainly occurs in Africa and Asia. Dracunculiasis is also known as Guinea-worm disease. In 2019, 53 cases were reported across four countries, a substantial decrease from 3,500,000 cases in 1986. It is not fatal, but can cause months of inactivity. It is caused by drinking water contaminated by water fleas infected with guinea-worm larvae. Approximately one year after infection, a painful blister forms and one or more worms emerge. Worms can be up to 1 metre long. It is usually treated by World Health Organization volunteers who clean and bandage wounds caused by worms and return daily to pull the worm out a few more inches. Dracunculiasis is preventable by water filtration, immediate case identification to prevent spread, health education, and treating ponds with larvicide. An eradication program has been able to reduce prevalence. As of 2014 [ update ] , the four endemic countries are Chad , Ethiopia , Mali , and South Sudan . The rate of echinococcosis is higher in rural areas, and there are more than one million people infected currently. It is caused by ingesting parasites in animal feces. There are two versions of the disease: cystic and alveolar . Both versions involve an asymptomatic incubation period of several years. In the cystic version, liver cysts cause abdominal pain , nausea , and vomiting , while cysts in the lungs cause chronic cough , chest pain , and shortness of breath . In alveolar echinococcosis, a primary cyst develops, usually in the liver, in addition to weight loss, abdominal pain, malaise , and signs of liver failure . Untreated alveolar echinococcosis is fatal. Surgery and drugs can be used to treat echinococcosis. It can be prevented by deworming dogs, sanitation, proper disposal of animal feces, health education, and livestock vaccination. Cystic echinococcosis is found in the eastern portion of the Mediterranean region, northern Africa, southern and eastern Europe, the southern portion of South America, and Central Asia. Alveolar echinococcosis is found in western and northern China, Russia, Europe, and northern North America. It can be diagnosed through imaging techniques and serological tests . There are limited data available on the prevalence of yaws , although it primarily affects children. The mortality risk is very low, but the disease causes disfigurement and disability if untreated. The most common symptom is skin lesions. It is a chronic bacterial infection, transmitted by skin contact, and caused by the spirochete bacterium Treponema pallidum pertenue . It is treated with antibiotics and can be prevented through hygiene and sanitation. Yaws is most prevalent in warm, moist tropical regions of the Americas, Africa, Asia, and the Pacific. Foodborne trematode infections include clonorchiasis , opisthorchiasis , fascioliasis , and paragonimiasis . These infections are all zoonotic , primarily affecting domestic or wild animals, but can also be transmitted to humans. They are acquired by eating food, such as raw fish, contaminated with the larval stages of the parasites. At least 40 million people are thought to be infected. African trypanosomiasis (African sleeping sickness) is a somewhat rare protozoal disease, with fewer than 10,000 cases currently. Human African trypanosomiasis is vector-borne and spreads through the bite of the tsetse fly . The most common symptoms are fever, headache, lymphadenopathy , sleeping disturbances, personality changes, cognitive decline, and coma . The disease is always fatal if untreated. The current forms of treatment are highly toxic and ineffective, as resistance is spreading. It is diagnosed through an inexpensive serological test. [ medical citation needed ]The three forms of leishmaniasis , a protozoal disease, are visceral ( Kala-azar ), cutaneous , and mucocutaneous. There are an estimated 12 million people infected. It is fatal if untreated, and 20,000 deaths from visceral leishmaniasis occur annually. It is a vector-borne disease caused by the bite of sandflies . At least 90 percent of visceral leishmaniasis occurs in Bangladesh , Brazil , Ethiopia , India , South Sudan , and Sudan . Cutaneous leishmaniasis occurs in Afghanistan , Algeria , Brazil, Colombia , Iran , Pakistan , Peru , Saudi Arabia , and Syria . Around 90 percent of mucocutaneous leishmaniasis occurs in Bolivia , Brazil, and Peru. A vaccine is under development to prevent leishmaniasis. The only other method of prevention is avoidance of sandfly bites. Diagnosis can be made by clinical signs, serological tests, or parasitological tests. Leishmaniasis can be treated with expensive medications. According to recent figures from the WHO, 208,619 new cases of leprosy were reported in 2018 from 127 countries. It is most prevalent in India (69% of cases), Brazil, Indonesia , Nigeria , the Democratic Republic of the Congo , Madagascar , and East Africa from Mozambique to Ethiopia, with the highest relative incidence in India, Brazil, and Nepal . There are one to two million individuals currently disabled or disfigured due to past or present leprosy. It is caused by bacteria and transmitted through droplets from the mouth and nose of infected individuals. Leprosy causes disfigurement and physical disabilities if untreated. It is curable if treated early. Treatment requires multidrug therapy. The BCG vaccine has some preventative effect against leprosy. Leprosy has a 5–20 year incubation period, and the symptoms are damage to the skin, nerves, eyes, and limbs. Lymphatic filariasis is also known as elephantiasis . There are approximately 120 million individuals infected and 40 million with deformities. Approximately two-thirds of cases are in Southwest Asia, and one-third are in Africa. Lymphatic filariasis is rarely fatal but has lifelong implications, such as lymphoedema of the limbs, genital disease, and painful recurrent attacks. Most people are asymptomatic but have lymphatic damage. Up to 40 percent of infected individuals have kidney damage. It is a vector-borne disease, caused by nematode worms that are transmitted by mosquitoes. It can be treated with cost-effective antihelminthic treatments, and washing skin can slow or even reverse damage. It is diagnosed with a finger-prick blood test. Noma, an opportunistic bacterial infection causing gangrenous necrosis of the mouth, was added to the World Health Organization's list of neglected tropical diseases in December 2023. Onchocerciasis is also known as river blindness. There are 20.9 million people infected, and prevalence is higher in rural areas. Over 99 percent of cases are in sub-Saharan Africa . It causes blindness, skin rashes, lesions, intense itching, and skin depigmentation. It is a vector-borne disease, caused by blackflies infected with filarial worms. It can be treated with ivermectin and prevented by insecticide spraying or preventative dosing with ivermectin. There are two forms of rabies : furious and paralytic. It is mostly found in Asia and Africa. There is a higher prevalence in rural areas, and it disproportionately affects children. Rabies is fatal after symptoms develop. It is caused by a lyssavirus transmitted through wounds or bites from infected animals. The first symptoms are fever and pain near the infection site, which occur after a one- to three-month incubation period. Furious rabies (the more common type) causes hyperactivity, hydrophobia, and aerophobia; death by cardio-respiratory arrest occurs within days. Paralytic rabies causes a slow progression from paralysis to coma to death. There are 60,000 deaths from rabies annually. It can be prevented in dogs by vaccination and by cleaning and disinfecting bite wounds and post-exposure prophylaxis . Rabies is undiagnosable before symptoms develop. It can be detected through tissue testing after symptoms develop. There are over 200 million cases of schistosomiasis . Approximately 85 percent of cases are in sub-Saharan Africa. The disease can be fatal by causing bladder cancer and hematemesis . Schistosoma species have a complex life cycle that alternates between humans and freshwater snails. Infection occurs when the skin comes into contact with contaminated fresh water in which snails that carry the parasite are living. Symptoms for schistosomiasis are not caused by the worms but by the body's reaction to the eggs. The eggs that do not pass out of the body can become lodged in the intestine or bladder, causing inflammation or scarring. Children who are repeatedly infected can develop anemia, malnutrition, and learning difficulties. The symptoms are usually haematuria , bladder obstruction, renal failure , bladder cancer , periportal fibrosis, bladder fibrosis, liver fibrosis, portal hypertension , cervical lesions, ascites , and esophageal varices . Inexpensive praziquantel can be used to treat individuals with schistosomiasis, but it cannot prevent reinfection. The cost of prevention is US$0.32 per child per year. Mass deworming treatment with praziquantel, better access to safe water, sanitation, and health education can all be used to prevent schistosomiasis. Vaccines are under development. It can be diagnosed through a serological test, but the test often produces false negatives. Soil-transmitted helminthiasis is the most prevalent neglected tropical disease. The four major worm species responsible for soil-transmitted helminthiasis are Ascaris ( roundworms ), Trichuris ( whipworm ), the hookworms Necator americanus and Ancylostoma duodenale , and Strongyloides stercoralis . There are 1.5 billion people currently infected. Soil-transmitted helminthiasis occurs in sub-Saharan Africa, the Americas, China, and East Asia. The mortality risk is very low. The most common symptoms are anemia, stunted growth , intestinal problems, lack of energy, and compromised physical and cognitive development. Infected children often fall behind in schooling. The severity of symptoms depends on the number of worms in the body. Parasitic worms are generally transmitted via exposure to infected human feces and soil that are spread in the environment, for example, due to open defecation . The most common treatment is medicine. It can be prevented through hygienically prepared food and clean water, improved sanitation , periodic deworming, and health education. The World Health Organization recommends mass deworming without prior diagnosis. Cysticercosis is a tapeworm larvae infection, while taeniasis is infection with adult tapeworms . Both are found in Asia, Africa, and Latin America, particularly on farms in which pigs are exposed to human excrement. Cysticercosis is the most common preventable cause of epilepsy in the developing world. Cysticercosis occurs after ingestion of contaminated food, water, or soil. Cysts and lesions can cause headaches , blindness , seizures , hydrocephalus , meningitis , and dementia . Neurocysticercosis , or the parasitic infection of the nervous system, can be fatal. Taeniasis is not fatal. It is usually contracted after eating undercooked contaminated pork. Taeniasis has mild symptoms, including abdominal pain, nausea, diarrhea, or constipation. [ citation needed ] Drugs are used to treat both diseases. Infection can be prevented through stricter meat-inspection standards, livestock confinement, improved hygiene and sanitation, health education, safe meat preparation, and identifying and treating human and pig carriers. There are 21.4 million people infected with trachoma , of whom 2.2 million are partially blind and 1.2 million are blind. It is found in Africa, Asia, Central and South America, the Middle East, and Australia. The disease disproportionately affects women and children. The mortality risk is very low, although multiple re-infections eventually lead to blindness. The symptoms are internally scarred eyelids, followed by eyelids turning inward. Trachoma is caused by a micro-organism that spreads through eye discharges (on hands, cloth, etc.) and by "eye-seeking flies". It is treated with antibiotics. The only known prevention method is interpersonal hygiene. [ citation needed ]Chromoblastomycosis is a long-term fungal infection of the skin and subcutaneous tissue (a chronic subcutaneous mycosis ). It can be caused by many different types of fungi which become implanted under the skin , often by thorns or splinters. Chromoblastomycosis spreads very slowly. [ citation needed ] Other important endemic mycoses with common systemic involvement are histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, blastomycosis and talaromycosis. These infections are also seldomly seen in returning travelers in western countries Snakebite was added to the list in 2017, after years of criticism of the WHO by activists for not making it a priority. The greatest burden of snakebite morbidity is in India and Southeast Asia. Globally, there are an estimated 421,000 envenomings each year (about 1 in 4 snakebites) and 20,000 deaths, but snakebites often go unreported. A policy analysis however found that the placement of snakebite in the global health agenda of WHO is fragile due to reluctance acceptance of the disease in the neglected tropical disease community and the perceived colonial nature of the network driving the agenda. Several NTDs, such as leprosy , cause severe deformities that result in social stigma. Stigma is considered to be the "hidden burden" of NTDs and is not accounted for in measures such as disability-adjusted life years (DALYs). Other NTDs that carry heavy social stigma include onchocerciasis , lymphatic filariasis , plague , Buruli ulcer , leishmaniasis , and Chagas disease . Lymphatic filariasis, for example, causes severe deformities that can result in denial of marriage and inability to work. Studies in Ghana and Sri Lanka have demonstrated that support groups for patients with lymphatic filariasis can increase participants' self-esteem, quality of life, and social relations through social support and providing practical advice on how to manage their illness. The social effects of neglected tropical diseases have been shown to affect men and women in different ways. Men are socially stigmatized in a way that detrimentally affects their economic prospects. Women are more likely to be affected in the areas of marriage and family. A 2012 review found that infection with a neglected tropical disease predisposes individuals to poor mental health. This is partially due to the social stigma that surrounds NTDs, but is also likely caused by the subsequent lack of access to health and social services. Overall, being a member of the infected community was found to cut individuals off from multiple aspects of society via civic rights, educational opportunities, and employment. A high prevalence of post-traumatic stress disorder (PTSD) and depression was found among people who had survived snakebites. More research needs to be directed to understanding psychological aspects of NTDs to understand their effects more fully and to direct strategies to manage them better in healthcare systems where mental health professionals are scarce. NTDs disproportionately affect women and children. There is also added risk of hookworm infection during pregnancy and potential to transfer diseases such as Chagas during pregnancy. A study in Uganda found that women were able to obtain treatment more easily than men because they had fewer occupational responsibilities and were more trusting of treatments, but ignorance of the effects of medicines during pregnancy prevented adequate care. The paper concludes that gender should be considered when designing treatment programs in Uganda. Additionally, women often bear a heavier social stigma in relation to the pressure to marry. [ dubious – discuss ] [ failed verification ] The cost of treatment of some of these diseases, such as Buruli ulcer, can be almost the average household income for families in the highest quarter of incomes, while for those in the lowest quarter it can be over twice the yearly income. These enormous financial costs often cause deferral of treatment and financial ruin. These diseases also cost the government in terms of healthcare provision and lost worker productivity through morbidity and shortened life spans. In Kenya, for example, deworming is estimated to increase average adult income by 40 percent, which is a benefit-to-cost ratio of 100. Each untreated case of trachoma is estimated to cost US$118 in lost productivity. Each case of schistosomiasis causes a loss of 45.4 days of work per year. Most of the diseases cost the economies of developing countries millions of dollars. Large-scale prevention campaigns are predicted to increase agricultural output and education levels. The low cost of treatment for NTDs can be attributed to the large scale of the programs, free provision of drugs by pharmaceutical companies, delivery modes of drugs, and unpaid volunteers who distribute the drugs. The economic burden of NTDs is undervalued and therefore the corresponding economic effect and cost-effectiveness of decreasing prevalence of NTDs is underestimated. The investment return on measures to control NTDs is estimated to be between 14 and 30 percent, depending on the disease and region. Coinfection is a major concern with NTDs, making them more damaging than their mortality rates might suggest. Because factors such as poverty, inadequate healthcare and inadequate sanitation practices contribute to all NTDs, they are often found in overlapping distributions. Helminth infections , as the most common infection of humans, are often found to be in multi-infection systems. For example, in Brazil, low socioeconomic status contributes to overcrowded housing. In these same areas, coinfection by Necator americanus and Schistosoma mansoni is common. The effect of each worm weakens the immune system , making infection from the other more likely and more severe. For this reason, coinfection carries a higher risk of mortality. NTDs may also play a role in infection with other diseases, such as malaria , HIV/AIDS , and tuberculosis . The ability of helminths to manipulate the immune system may create a physiological environment that could exacerbate the progression of HIV/AIDS. Some evidence from Senegal , Malawi , and Thailand has shown that helminth infections raise the risk of malarial infection. Several NTDs, such as leprosy , cause severe deformities that result in social stigma. Stigma is considered to be the "hidden burden" of NTDs and is not accounted for in measures such as disability-adjusted life years (DALYs). Other NTDs that carry heavy social stigma include onchocerciasis , lymphatic filariasis , plague , Buruli ulcer , leishmaniasis , and Chagas disease . Lymphatic filariasis, for example, causes severe deformities that can result in denial of marriage and inability to work. Studies in Ghana and Sri Lanka have demonstrated that support groups for patients with lymphatic filariasis can increase participants' self-esteem, quality of life, and social relations through social support and providing practical advice on how to manage their illness. The social effects of neglected tropical diseases have been shown to affect men and women in different ways. Men are socially stigmatized in a way that detrimentally affects their economic prospects. Women are more likely to be affected in the areas of marriage and family. A 2012 review found that infection with a neglected tropical disease predisposes individuals to poor mental health. This is partially due to the social stigma that surrounds NTDs, but is also likely caused by the subsequent lack of access to health and social services. Overall, being a member of the infected community was found to cut individuals off from multiple aspects of society via civic rights, educational opportunities, and employment. A high prevalence of post-traumatic stress disorder (PTSD) and depression was found among people who had survived snakebites. More research needs to be directed to understanding psychological aspects of NTDs to understand their effects more fully and to direct strategies to manage them better in healthcare systems where mental health professionals are scarce. NTDs disproportionately affect women and children. There is also added risk of hookworm infection during pregnancy and potential to transfer diseases such as Chagas during pregnancy. A study in Uganda found that women were able to obtain treatment more easily than men because they had fewer occupational responsibilities and were more trusting of treatments, but ignorance of the effects of medicines during pregnancy prevented adequate care. The paper concludes that gender should be considered when designing treatment programs in Uganda. Additionally, women often bear a heavier social stigma in relation to the pressure to marry. [ dubious – discuss ] [ failed verification ]Several NTDs, such as leprosy , cause severe deformities that result in social stigma. Stigma is considered to be the "hidden burden" of NTDs and is not accounted for in measures such as disability-adjusted life years (DALYs). Other NTDs that carry heavy social stigma include onchocerciasis , lymphatic filariasis , plague , Buruli ulcer , leishmaniasis , and Chagas disease . Lymphatic filariasis, for example, causes severe deformities that can result in denial of marriage and inability to work. Studies in Ghana and Sri Lanka have demonstrated that support groups for patients with lymphatic filariasis can increase participants' self-esteem, quality of life, and social relations through social support and providing practical advice on how to manage their illness. The social effects of neglected tropical diseases have been shown to affect men and women in different ways. Men are socially stigmatized in a way that detrimentally affects their economic prospects. Women are more likely to be affected in the areas of marriage and family. A 2012 review found that infection with a neglected tropical disease predisposes individuals to poor mental health. This is partially due to the social stigma that surrounds NTDs, but is also likely caused by the subsequent lack of access to health and social services. Overall, being a member of the infected community was found to cut individuals off from multiple aspects of society via civic rights, educational opportunities, and employment. A high prevalence of post-traumatic stress disorder (PTSD) and depression was found among people who had survived snakebites. More research needs to be directed to understanding psychological aspects of NTDs to understand their effects more fully and to direct strategies to manage them better in healthcare systems where mental health professionals are scarce. NTDs disproportionately affect women and children. There is also added risk of hookworm infection during pregnancy and potential to transfer diseases such as Chagas during pregnancy. A study in Uganda found that women were able to obtain treatment more easily than men because they had fewer occupational responsibilities and were more trusting of treatments, but ignorance of the effects of medicines during pregnancy prevented adequate care. The paper concludes that gender should be considered when designing treatment programs in Uganda. Additionally, women often bear a heavier social stigma in relation to the pressure to marry. [ dubious – discuss ] [ failed verification ]The cost of treatment of some of these diseases, such as Buruli ulcer, can be almost the average household income for families in the highest quarter of incomes, while for those in the lowest quarter it can be over twice the yearly income. These enormous financial costs often cause deferral of treatment and financial ruin. These diseases also cost the government in terms of healthcare provision and lost worker productivity through morbidity and shortened life spans. In Kenya, for example, deworming is estimated to increase average adult income by 40 percent, which is a benefit-to-cost ratio of 100. Each untreated case of trachoma is estimated to cost US$118 in lost productivity. Each case of schistosomiasis causes a loss of 45.4 days of work per year. Most of the diseases cost the economies of developing countries millions of dollars. Large-scale prevention campaigns are predicted to increase agricultural output and education levels. The low cost of treatment for NTDs can be attributed to the large scale of the programs, free provision of drugs by pharmaceutical companies, delivery modes of drugs, and unpaid volunteers who distribute the drugs. The economic burden of NTDs is undervalued and therefore the corresponding economic effect and cost-effectiveness of decreasing prevalence of NTDs is underestimated. The investment return on measures to control NTDs is estimated to be between 14 and 30 percent, depending on the disease and region. Coinfection is a major concern with NTDs, making them more damaging than their mortality rates might suggest. Because factors such as poverty, inadequate healthcare and inadequate sanitation practices contribute to all NTDs, they are often found in overlapping distributions. Helminth infections , as the most common infection of humans, are often found to be in multi-infection systems. For example, in Brazil, low socioeconomic status contributes to overcrowded housing. In these same areas, coinfection by Necator americanus and Schistosoma mansoni is common. The effect of each worm weakens the immune system , making infection from the other more likely and more severe. For this reason, coinfection carries a higher risk of mortality. NTDs may also play a role in infection with other diseases, such as malaria , HIV/AIDS , and tuberculosis . The ability of helminths to manipulate the immune system may create a physiological environment that could exacerbate the progression of HIV/AIDS. Some evidence from Senegal , Malawi , and Thailand has shown that helminth infections raise the risk of malarial infection. Coinfection is a major concern with NTDs, making them more damaging than their mortality rates might suggest. Because factors such as poverty, inadequate healthcare and inadequate sanitation practices contribute to all NTDs, they are often found in overlapping distributions. Helminth infections , as the most common infection of humans, are often found to be in multi-infection systems. For example, in Brazil, low socioeconomic status contributes to overcrowded housing. In these same areas, coinfection by Necator americanus and Schistosoma mansoni is common. The effect of each worm weakens the immune system , making infection from the other more likely and more severe. For this reason, coinfection carries a higher risk of mortality. NTDs may also play a role in infection with other diseases, such as malaria , HIV/AIDS , and tuberculosis . The ability of helminths to manipulate the immune system may create a physiological environment that could exacerbate the progression of HIV/AIDS. Some evidence from Senegal , Malawi , and Thailand has shown that helminth infections raise the risk of malarial infection. Prevention and eradication are important because "of the appalling stigma, disfigurement, blindness and disabilities caused by NTDs." The principal aim of the London Declaration on Neglected Tropical Diseases was the elimination or eradication of dracunculiasis , leprosy , lymphatic filariasis , onchocerciasis , trachoma , sleeping sickness , visceral leishmaniasis , and canine rabies within ten years of its launch in January 2012. The declaration is a collaborative effort involving the WHO, the World Bank , the Bill & Melinda Gates Foundation, the world's 13 leading pharmaceutical companies, and government representatives from the US, UK, United Arab Emirates, Bangladesh, Brazil, Mozambique, and Tanzania. While there has been a noticeable uptick in biological research into NTDs, prevention may be supplemented by social and development outreach. Spiegel and coauthors advocated for "social offset", which reallocates some funding for biotechnological research to social programs. This attempts to alleviate some of the factors (such as poverty, poor sanitation, overcrowding and poor healthcare) that greatly exacerbate conditions brought on by NTDs. Projects such as these also strengthen the goal of sustained eliminations rather than quickly addressing symptoms. There are many prevention and eradication campaigns funded by organizations such as the World Health Organization, US Agency for International Development , Bill & Melinda Gates Foundation , and UK Department for International Development . Sustainable Development Goal 3 has the target: "By 2030, [to] end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases ." In 2012, WHO published an NTD "roadmap", which contained milestones for 2015 and 2020, and specified targets for eradication, elimination and intensified control of the different NTDs. For example: In 2021, WHO updated their NTD roadmap "Together towards 2030", outlining their approach for 2021–2030. : v–vi The U.S. Food and Drug Administration priority review voucher is an incentive for companies to invest in new drugs and vaccines for tropical diseases. A provision of the Food and Drug Administration Amendments Act of 2007 awards a transferable "priority review voucher" to any company that obtains approval for a treatment for one of the listed diseases. The voucher can later be used to accelerate the review of an unrelated drug. This program is for all tropical diseases and includes medicines for malaria and tuberculosis. The first voucher given was for Coartem , a malaria treatment. The prize was proposed by Duke University faculty Henry Grabowski, Jeffrey Moe, and David Ridley in their 2006 Health Affairs paper "Developing Drugs for Developing Countries". In 2007, United States Senators Sam Brownback (R-KS) and Sherrod Brown (D-OH) sponsored an amendment to the Food and Drug Administration Amendments Act of 2007. President George W. Bush signed the bill in September 2007. [ citation needed ] Deworming treatments in infected children may have some nutritional benefit, as worms are often partially responsible for malnutrition. However, in areas where these infections are common, there is strong evidence that mass deworming campaigns do not have a positive effect on children's average nutritional status, levels of blood haemoglobin , cognitive abilities, performance at school, or survival. To achieve health gains in the longer term, improvements in sanitation and hygiene behaviours are also required, together with deworming treatments. [ citation needed ] The effect of mass deworming on school attendance is disputed. It has been argued that mass deworming has a positive effect on school attendance. The long-term benefits of deworming include a decrease in school absenteeism by 25 percent and an increase in adult earnings by 20 percent. A systematic review, however, found that there is little or no difference in attendance in children who receive mass deworming compared to children who did not. One study found that boys were enrolled in primary school for more years than boys who were in schools that did not offer such programs. Girls in the same study were about a quarter more likely to attend secondary school if they received treatment. Both groups went on to participate in more skilled sectors of the labor market. The economic growth generated from school programs such as this may balance out the actual expenses of the program. However, the results of this study are disputed (due to a high risk of bias in the study), and the positive long-term outcomes of mass deworming remain unclear. Inclusion of NTDs into initiatives for malaria , HIV/AIDS , and tuberculosis , as well as integration of NTD treatment programs, may have advantages given the strong link between these diseases and NTDs. Some neglected tropical diseases share common vectors (sandflies, black flies, and mosquitos). Both medicinal and vector control efforts may be combined. A four-drug rapid-impact package has been proposed that targets multiple diseases together. This package is estimated to cost US$0.40 per patient, with estimated saving of 26–47% compared to treating the diseases separately. While more research must be done in order to understand how NTDs and other diseases interact in both the vector and the human stages, safety assessments have so far produced positive results. Many neglected tropical diseases and other prevalent diseases share common vectors, creating another opportunity for treatment and control integration. One such example of this is malaria and lymphatic filariasis, which are both transmitted by the same or related mosquito vectors. Vector control, through the distribution of insecticide-treated nets, reduces human contact with a wide variety of disease vectors. Integrated vector control may also alleviate pressure on mass drug administration, especially with respect to rapidly evolving drug resistance. Combining vector control and mass drug administration deemphasizes both, making each less susceptible to resistance evolution. Water, sanitation, and hygiene ( WASH ) interventions are essential in preventing many NTDs, such as soil-transmitted helminthiasis . Mass drug administration alone will not protect people from re-infection. A more holistic and integrated approach to NTDs and WASH efforts will benefit both sectors along with the communities they are aiming to serve. This is especially true in areas where more than one NTD is endemic. In August 2015, the World Health Organization unveiled a global strategy and action plan to integrate WASH with other public health interventions to accelerate the elimination of NTDs. The plan aimed to intensify control or eliminate certain NTDs in specific regions by 2020, and referred to the NTD "roadmap" milestones from 2012 that included eradication of dracunculiasis by 2015 and of yaws by 2020, elimination of trachoma and lymphatic filariasis as public health problems by 2020, and intensified control of dengue, schistosomiasis, and soil-transmitted helminthiases. Closer collaboration between WASH and NTD programmes can lead to synergies . They can be achieved through collaborative planning, delivery and evaluation of programmes, strengthening and sharing of evidence, and using monitoring tools to improve the equity of health services. Reasons why WASH plays an important role in NTD prevention and patient care include: Biotechnology companies in the developing world have targeted neglected tropical diseases due to a need to improve global health. Mass drug administration is considered a possible method for eradication, especially for lymphatic filariasis, onchocerciasis, and trachoma, although drug resistance is a potential problem. According to Fenwick, Pfizer donated 70 million doses of drugs in 2011 to eliminate trachoma through the International Trachoma Initiative. Merck has helped The African Programme for the Control of Onchocerciasis (APOC) and Oncho Elimination Programme for the Americas to greatly diminish the effect of onchocerciasis by donating ivermectin . Merck KGaA pledged to give 200 million tablets of praziquantel , the only cure for schistosomiasis , over 10 years. GlaxoSmithKline has donated two billion tablets of medicine for lymphatic filariasis and pledged 400 million deworming tablets per year for five years in 2010. Johnson & Johnson has pledged 200 million deworming tablets per year. Novartis has pledged leprosy treatment, and EISAI pledged two billion tablets to help treat lymphatic filariasis. Non-governmental organizations that focus exclusively on NTDs include the Schistosomiasis Control Initiative , Deworm the World , and the END Fund. Despite under-funding, treatment and prevention of many neglected diseases is cost-effective. The cost of treating a child for infection of soil-transmitted helminths and schistosomes (some of the main causes of neglected diseases) is less than US$0.50 per year when administered as part of school-based mass deworming by Deworm the World. This programme is recommended by Giving What We Can and the Copenhagen Consensus Centre as one of the most efficient and cost-effective solutions. The efforts of the Schistosomiasis Control Initiative to combat neglected diseases include the use of rapid-impact packages: supplying schools with packages including four or five drugs, and training teachers in how to administer them. [ citation needed ] Health Action International based in Amsterdam worked with the WHO to get snakebite envenoming on the list of neglected tropical diseases. An alternative to the profit-driven drug development model emerged in 2000 to address the needs of these neglected patients. Product development partnerships (PDPs) aim at implementing and accelerating the research and development (R&D) of safe and effective health tools (diagnostics, vaccines, drugs) to combat neglected diseases. Drugs for Neglected Disease initiative (DNDi) is one of these PDPs that has already developed new treatments for NTDs. The Sabin Vaccine Institute , founded in 1993, works to address the issues of vaccine-preventable diseases as well as NTDs. They run three main programs: Sabin Vaccine Development, Global Network for Neglected Tropical Diseases , and Vaccine Advocacy and Education. Their product development partnership affiliates them with the Texas Children's Hospital as well as the Baylor College of Medicine . Their major campaign, End7, aims to end seven of the most common NTDs ( elephantiasis , river blindness , snail fever , trachoma , roundworm , whipworm , and hookworm ) by 2020. Through End7, college campuses undertake fundraising and educational initiatives for the broader goals of the campaign. WIPO Re:Search was established in 2011 by the World Intellectual Property Organization in collaboration with BIO Ventures for Global Health (BVGH) and with the active participation of leading pharmaceutical companies and other private and public sector research organizations. It allows organizations to share their intellectual property, compounds, expertise, facilities, and know-how royalty-free with qualified researchers worldwide working on new solutions for NTDs, malaria, and tuberculosis. In 2013, the Government of Japan, five Japanese pharmaceutical companies, the Bill and Melinda Gates Foundation, and the UNDP established a new public–private partnership, the Global Health Innovative Technology Fund . They pledged over US$100 million to the fund over five years, to be awarded as grants to R&D partnerships across sectors in Japan and elsewhere, working to develop new drugs and vaccines for 17 neglected diseases, in addition to HIV, malaria, and tuberculosis. Affordability of the resulting drugs and vaccines is one of the key criteria for grant awards. The London Declaration on Neglected Tropical Diseases, initiated by the Bill and Melinda Gates Foundation launched on 30 January 2012 in London. Inspired by the WHO roadmap to eradicate or prevent transmission for neglected tropical diseases, it aimed to eradicate or reduce NTDs by the year 2020. It was endorsed by governments and organisations around the world, as well as major pharmaceutical companies including Abbott , AstraZeneca , Bayer HealthCare Pharmaceuticals , Becton Dickinson , Bristol-Myers Squibb , Eisai , Gilead Sciences , GlaxoSmithKline , Johnson & Johnson , Merck KGaA , Merck Sharp & Dohme, MSD , Novartis , Pfizer , and Sanofi . It was not a complete success, but millions of lives were saved, the burden of the infections was reduced, and 42 countries eliminated at least one disease. To commemorate the programme, WHO adopted 30 January as the World NTD Day . The Kigali Declaration on Neglected Tropical Diseases was launched at the Kigali Summit on Malaria and Neglected Tropical Diseases (NTDs) hosted by the Government of Rwanda at its capital city Kigali on 23 June 2022. It was signed as a support for the World Health Organization 's 2021–30 road map for NTDs and the target of Sustainable Development Goal 3 to end NTD epidemics; and as a follow-up project of the London Declaration . Supported by WHO, governments of the Commonwealth of Nations pledged the endorsement, along with commitments from GSK plc , Novartis , and Pfizer . An open-access journal dedicated to neglected tropical diseases called PLoS Neglected Tropical Diseases first began publication in 2007. One of the first large-scale initiatives to address NTDs came from a collaboration between Kenneth Warren and the Rockefeller Foundation . Ken Warren is regarded as a pioneer in neglected tropical disease research. The Great Neglected Tropical Diseases Network was a consortium of scientists from all over the world, hand-picked by Warren, working to expand the research base in neglected diseases. Many of the scientists that he recruited had not been involved in NTD research before. The network ran from 1978 to 1988. Warren's vision was to establish units within biological labs across the world, dedicated to R&D . By forming a critical mass of scientists in NTD research, he hoped to attract new students into the field. The interdisciplinary group met annually to update the community on research progress. Much of the work done by this group focused on understanding the mechanisms behind infection. At these informally structured meetings, research partnerships were formed. Warren himself encouraged these partnerships, especially if they bridged the divide between developed and developing nations. Through the Great Neglected Tropical Disease Network, a great number of scientists were brought into the field of parasitology . There are many prevention and eradication campaigns funded by organizations such as the World Health Organization, US Agency for International Development , Bill & Melinda Gates Foundation , and UK Department for International Development . Sustainable Development Goal 3 has the target: "By 2030, [to] end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases ." In 2012, WHO published an NTD "roadmap", which contained milestones for 2015 and 2020, and specified targets for eradication, elimination and intensified control of the different NTDs. For example: In 2021, WHO updated their NTD roadmap "Together towards 2030", outlining their approach for 2021–2030. : v–vi The U.S. Food and Drug Administration priority review voucher is an incentive for companies to invest in new drugs and vaccines for tropical diseases. A provision of the Food and Drug Administration Amendments Act of 2007 awards a transferable "priority review voucher" to any company that obtains approval for a treatment for one of the listed diseases. The voucher can later be used to accelerate the review of an unrelated drug. This program is for all tropical diseases and includes medicines for malaria and tuberculosis. The first voucher given was for Coartem , a malaria treatment. The prize was proposed by Duke University faculty Henry Grabowski, Jeffrey Moe, and David Ridley in their 2006 Health Affairs paper "Developing Drugs for Developing Countries". In 2007, United States Senators Sam Brownback (R-KS) and Sherrod Brown (D-OH) sponsored an amendment to the Food and Drug Administration Amendments Act of 2007. President George W. Bush signed the bill in September 2007. [ citation needed ]In 2012, WHO published an NTD "roadmap", which contained milestones for 2015 and 2020, and specified targets for eradication, elimination and intensified control of the different NTDs. For example: In 2021, WHO updated their NTD roadmap "Together towards 2030", outlining their approach for 2021–2030. : v–viThe U.S. Food and Drug Administration priority review voucher is an incentive for companies to invest in new drugs and vaccines for tropical diseases. A provision of the Food and Drug Administration Amendments Act of 2007 awards a transferable "priority review voucher" to any company that obtains approval for a treatment for one of the listed diseases. The voucher can later be used to accelerate the review of an unrelated drug. This program is for all tropical diseases and includes medicines for malaria and tuberculosis. The first voucher given was for Coartem , a malaria treatment. The prize was proposed by Duke University faculty Henry Grabowski, Jeffrey Moe, and David Ridley in their 2006 Health Affairs paper "Developing Drugs for Developing Countries". In 2007, United States Senators Sam Brownback (R-KS) and Sherrod Brown (D-OH) sponsored an amendment to the Food and Drug Administration Amendments Act of 2007. President George W. Bush signed the bill in September 2007. [ citation needed ]Deworming treatments in infected children may have some nutritional benefit, as worms are often partially responsible for malnutrition. However, in areas where these infections are common, there is strong evidence that mass deworming campaigns do not have a positive effect on children's average nutritional status, levels of blood haemoglobin , cognitive abilities, performance at school, or survival. To achieve health gains in the longer term, improvements in sanitation and hygiene behaviours are also required, together with deworming treatments. [ citation needed ] The effect of mass deworming on school attendance is disputed. It has been argued that mass deworming has a positive effect on school attendance. The long-term benefits of deworming include a decrease in school absenteeism by 25 percent and an increase in adult earnings by 20 percent. A systematic review, however, found that there is little or no difference in attendance in children who receive mass deworming compared to children who did not. One study found that boys were enrolled in primary school for more years than boys who were in schools that did not offer such programs. Girls in the same study were about a quarter more likely to attend secondary school if they received treatment. Both groups went on to participate in more skilled sectors of the labor market. The economic growth generated from school programs such as this may balance out the actual expenses of the program. However, the results of this study are disputed (due to a high risk of bias in the study), and the positive long-term outcomes of mass deworming remain unclear. Inclusion of NTDs into initiatives for malaria , HIV/AIDS , and tuberculosis , as well as integration of NTD treatment programs, may have advantages given the strong link between these diseases and NTDs. Some neglected tropical diseases share common vectors (sandflies, black flies, and mosquitos). Both medicinal and vector control efforts may be combined. A four-drug rapid-impact package has been proposed that targets multiple diseases together. This package is estimated to cost US$0.40 per patient, with estimated saving of 26–47% compared to treating the diseases separately. While more research must be done in order to understand how NTDs and other diseases interact in both the vector and the human stages, safety assessments have so far produced positive results. Many neglected tropical diseases and other prevalent diseases share common vectors, creating another opportunity for treatment and control integration. One such example of this is malaria and lymphatic filariasis, which are both transmitted by the same or related mosquito vectors. Vector control, through the distribution of insecticide-treated nets, reduces human contact with a wide variety of disease vectors. Integrated vector control may also alleviate pressure on mass drug administration, especially with respect to rapidly evolving drug resistance. Combining vector control and mass drug administration deemphasizes both, making each less susceptible to resistance evolution. Water, sanitation, and hygiene ( WASH ) interventions are essential in preventing many NTDs, such as soil-transmitted helminthiasis . Mass drug administration alone will not protect people from re-infection. A more holistic and integrated approach to NTDs and WASH efforts will benefit both sectors along with the communities they are aiming to serve. This is especially true in areas where more than one NTD is endemic. In August 2015, the World Health Organization unveiled a global strategy and action plan to integrate WASH with other public health interventions to accelerate the elimination of NTDs. The plan aimed to intensify control or eliminate certain NTDs in specific regions by 2020, and referred to the NTD "roadmap" milestones from 2012 that included eradication of dracunculiasis by 2015 and of yaws by 2020, elimination of trachoma and lymphatic filariasis as public health problems by 2020, and intensified control of dengue, schistosomiasis, and soil-transmitted helminthiases. Closer collaboration between WASH and NTD programmes can lead to synergies . They can be achieved through collaborative planning, delivery and evaluation of programmes, strengthening and sharing of evidence, and using monitoring tools to improve the equity of health services. Reasons why WASH plays an important role in NTD prevention and patient care include: Biotechnology companies in the developing world have targeted neglected tropical diseases due to a need to improve global health. Mass drug administration is considered a possible method for eradication, especially for lymphatic filariasis, onchocerciasis, and trachoma, although drug resistance is a potential problem. According to Fenwick, Pfizer donated 70 million doses of drugs in 2011 to eliminate trachoma through the International Trachoma Initiative. Merck has helped The African Programme for the Control of Onchocerciasis (APOC) and Oncho Elimination Programme for the Americas to greatly diminish the effect of onchocerciasis by donating ivermectin . Merck KGaA pledged to give 200 million tablets of praziquantel , the only cure for schistosomiasis , over 10 years. GlaxoSmithKline has donated two billion tablets of medicine for lymphatic filariasis and pledged 400 million deworming tablets per year for five years in 2010. Johnson & Johnson has pledged 200 million deworming tablets per year. Novartis has pledged leprosy treatment, and EISAI pledged two billion tablets to help treat lymphatic filariasis. Non-governmental organizations that focus exclusively on NTDs include the Schistosomiasis Control Initiative , Deworm the World , and the END Fund. Despite under-funding, treatment and prevention of many neglected diseases is cost-effective. The cost of treating a child for infection of soil-transmitted helminths and schistosomes (some of the main causes of neglected diseases) is less than US$0.50 per year when administered as part of school-based mass deworming by Deworm the World. This programme is recommended by Giving What We Can and the Copenhagen Consensus Centre as one of the most efficient and cost-effective solutions. The efforts of the Schistosomiasis Control Initiative to combat neglected diseases include the use of rapid-impact packages: supplying schools with packages including four or five drugs, and training teachers in how to administer them. [ citation needed ] Health Action International based in Amsterdam worked with the WHO to get snakebite envenoming on the list of neglected tropical diseases. An alternative to the profit-driven drug development model emerged in 2000 to address the needs of these neglected patients. Product development partnerships (PDPs) aim at implementing and accelerating the research and development (R&D) of safe and effective health tools (diagnostics, vaccines, drugs) to combat neglected diseases. Drugs for Neglected Disease initiative (DNDi) is one of these PDPs that has already developed new treatments for NTDs. The Sabin Vaccine Institute , founded in 1993, works to address the issues of vaccine-preventable diseases as well as NTDs. They run three main programs: Sabin Vaccine Development, Global Network for Neglected Tropical Diseases , and Vaccine Advocacy and Education. Their product development partnership affiliates them with the Texas Children's Hospital as well as the Baylor College of Medicine . Their major campaign, End7, aims to end seven of the most common NTDs ( elephantiasis , river blindness , snail fever , trachoma , roundworm , whipworm , and hookworm ) by 2020. Through End7, college campuses undertake fundraising and educational initiatives for the broader goals of the campaign. WIPO Re:Search was established in 2011 by the World Intellectual Property Organization in collaboration with BIO Ventures for Global Health (BVGH) and with the active participation of leading pharmaceutical companies and other private and public sector research organizations. It allows organizations to share their intellectual property, compounds, expertise, facilities, and know-how royalty-free with qualified researchers worldwide working on new solutions for NTDs, malaria, and tuberculosis. In 2013, the Government of Japan, five Japanese pharmaceutical companies, the Bill and Melinda Gates Foundation, and the UNDP established a new public–private partnership, the Global Health Innovative Technology Fund . They pledged over US$100 million to the fund over five years, to be awarded as grants to R&D partnerships across sectors in Japan and elsewhere, working to develop new drugs and vaccines for 17 neglected diseases, in addition to HIV, malaria, and tuberculosis. Affordability of the resulting drugs and vaccines is one of the key criteria for grant awards. The London Declaration on Neglected Tropical Diseases, initiated by the Bill and Melinda Gates Foundation launched on 30 January 2012 in London. Inspired by the WHO roadmap to eradicate or prevent transmission for neglected tropical diseases, it aimed to eradicate or reduce NTDs by the year 2020. It was endorsed by governments and organisations around the world, as well as major pharmaceutical companies including Abbott , AstraZeneca , Bayer HealthCare Pharmaceuticals , Becton Dickinson , Bristol-Myers Squibb , Eisai , Gilead Sciences , GlaxoSmithKline , Johnson & Johnson , Merck KGaA , Merck Sharp & Dohme, MSD , Novartis , Pfizer , and Sanofi . It was not a complete success, but millions of lives were saved, the burden of the infections was reduced, and 42 countries eliminated at least one disease. To commemorate the programme, WHO adopted 30 January as the World NTD Day . The Kigali Declaration on Neglected Tropical Diseases was launched at the Kigali Summit on Malaria and Neglected Tropical Diseases (NTDs) hosted by the Government of Rwanda at its capital city Kigali on 23 June 2022. It was signed as a support for the World Health Organization 's 2021–30 road map for NTDs and the target of Sustainable Development Goal 3 to end NTD epidemics; and as a follow-up project of the London Declaration . Supported by WHO, governments of the Commonwealth of Nations pledged the endorsement, along with commitments from GSK plc , Novartis , and Pfizer . The London Declaration on Neglected Tropical Diseases, initiated by the Bill and Melinda Gates Foundation launched on 30 January 2012 in London. Inspired by the WHO roadmap to eradicate or prevent transmission for neglected tropical diseases, it aimed to eradicate or reduce NTDs by the year 2020. It was endorsed by governments and organisations around the world, as well as major pharmaceutical companies including Abbott , AstraZeneca , Bayer HealthCare Pharmaceuticals , Becton Dickinson , Bristol-Myers Squibb , Eisai , Gilead Sciences , GlaxoSmithKline , Johnson & Johnson , Merck KGaA , Merck Sharp & Dohme, MSD , Novartis , Pfizer , and Sanofi . It was not a complete success, but millions of lives were saved, the burden of the infections was reduced, and 42 countries eliminated at least one disease. To commemorate the programme, WHO adopted 30 January as the World NTD Day . The Kigali Declaration on Neglected Tropical Diseases was launched at the Kigali Summit on Malaria and Neglected Tropical Diseases (NTDs) hosted by the Government of Rwanda at its capital city Kigali on 23 June 2022. It was signed as a support for the World Health Organization 's 2021–30 road map for NTDs and the target of Sustainable Development Goal 3 to end NTD epidemics; and as a follow-up project of the London Declaration . Supported by WHO, governments of the Commonwealth of Nations pledged the endorsement, along with commitments from GSK plc , Novartis , and Pfizer . An open-access journal dedicated to neglected tropical diseases called PLoS Neglected Tropical Diseases first began publication in 2007. One of the first large-scale initiatives to address NTDs came from a collaboration between Kenneth Warren and the Rockefeller Foundation . Ken Warren is regarded as a pioneer in neglected tropical disease research. The Great Neglected Tropical Diseases Network was a consortium of scientists from all over the world, hand-picked by Warren, working to expand the research base in neglected diseases. Many of the scientists that he recruited had not been involved in NTD research before. The network ran from 1978 to 1988. Warren's vision was to establish units within biological labs across the world, dedicated to R&D . By forming a critical mass of scientists in NTD research, he hoped to attract new students into the field. The interdisciplinary group met annually to update the community on research progress. Much of the work done by this group focused on understanding the mechanisms behind infection. At these informally structured meetings, research partnerships were formed. Warren himself encouraged these partnerships, especially if they bridged the divide between developed and developing nations. Through the Great Neglected Tropical Disease Network, a great number of scientists were brought into the field of parasitology . The distribution of neglected tropical disease disproportionally affects about one billion of the world's poorest populations, causing mortality, disability, and morbidity. Lack of funding, resources, and attention can result in treatable and preventable diseases causing death. Factors like political dynamics, poverty, and geographical conditions can make the delivery of NTD control programs difficult. Intersectional collaboration of poverty reduction policies and neglected tropical diseases creates cross-sector approaches to simultaneously address these issues. The six most common NTDs include soil-transmitted helminths (STHs)—specifically roundworms ( Ascaris lumbricoides ), whipworm ( Trichuris trichiura ), and hookworms ( Necator americanus and Ancylostoma duodenale )—schistosomiasis, trachoma, and lymphatic filariasis (LF). These diseases affect one-sixth of the world's population, with 90 percent of the disease burden occurring in sub-Saharan Africa. Information on the frequency of neglected tropical diseases is of low quality. It is currently difficult to summarize all of the information on this family of diseases. One effort to do so is the Global Burden of Disease framework. It aims to create a standardized method of measurement. The principle components of the approach involve 1) the measuring of premature mortality as well as disability, 2) the standardized usage of DALYs ( disability-adjusted life years ), and 3) widespread inclusion of diseases and injury causes with the estimation of missing data. However, the DALY has been criticized as a "systematic undervaluation" of disease burden. King asserts that DALY emphasizes the individual too much while ignoring the effects of the ecology of the disease. In order for the measure to become more valid, it may have to take the context of poverty more into account. King also emphasizes that DALYs may not capture the non-linear effects of poverty on the cost-utility analysis of disease control. The Socio-Demographic Index (SDI) and Healthy Life Expectancy (HALE) are other summary measures that can be used to take into account other factors. HALE is a metric that weights years lived and health loss before death to provide a summary of population health. SDI is a measurement that includes lag-distributed income per capita, average education, and fertility rate. Socioeconomic factors greatly influence the distribution of neglected tropical diseases, and not addressing these factors in models and measurements can lead to ineffective public health policy. NTD interventions include programs to address environmental and social determinants of health (e.g., vector control, water quality, sanitation) as well as programs offering mass drug administration for disease prevention and treatment. Drug treatments exist to confront many of the NTDs and represent some of the world's essential medicines . Despite significant health and economic improvements using available medicines, the low number of new compounds being researched and developed for NTDs is an ongoing and significant challenge. The dearth of candidates in pharmaceutical company drug pipelines is primarily attributed to the high costs of drug development and the fact that NTDs are concentrated among the world's poor. Other disincentives to investment include weak existing infrastructure for distribution and sales as well as concerns regarding intellectual property protection. However, the major stakeholders in NTD drug development—governments, foundations, pharmaceutical companies, academia, and NGOs —are involved in activities to help address the research and development shortfall and meet the many challenges presented by neglected tropical diseases. Initiatives include public-private partnerships, global R&D capacity building, priority vouchers to speed drug approval processes, open source scientific collaborations, and harmonization of global governance structures concerning NTDs. [ citation needed ] The diseases considered neglected tropical diseases vary. Some researchers no longer consider malaria , HIV , and tuberculosis to be neglected due to the amount of public attention and increased funding they have received. Outside "The Big Three", the seven most prevalent neglected tropical diseases in order of their global prevalence are ascariasis , trichuriasis , hookworm infection , schistosomiasis , lymphatic filariasis , and trachoma . These seven are among a larger list of thirteen major NTDs: onchocerciasis , leishmaniasis , Chagas disease , leprosy , human African trypanosomiasis (sleeping sickness), dracunculiasis , and Buruli ulcer . In their 2002 review of the U.S. Food and Drug Administration (FDA) databases and the European Agency for the Evaluation of Medicinal Products , Troullier et al. found that 16 out of 1393 new chemical entities were approved for NTDs between 1975 and 1999 (~1%). Cohen et al. revisited the data and using the same methodology found 32 new chemical entities during the time period. In a second analysis using an expanded list of NTDs based on the G-FINDER survey, the number was slightly higher, with 46 new drugs and vaccines approved (~3% of the total including HIV drugs). Between 2000 and 2009, there has been some increase with an additional 26 newly approved drugs and vaccines for NTDs. A number of factors are recognized as contributing to the low number. The barrier most reported is the high cost of drug development. Estimates are that pharmaceutical companies' development costs to approval fall between $500 million and $2 billion. DiMasi, Hansen, and Grabowski calculated an average of $802 million in year 2000 dollars. Furthermore, the time that drugs are approved for use averages seven years out of the twenty years on patent, meaning a tendency for the market to focus on diseases of developed nations where high prices can be used to recoup research and development costs, and subsidize failed R&D efforts. In short, NTD research and development is considered a high investment risk, given that NTDs predominantly affect the poor in low- and middle-income countries. Additional barriers include drug safety regulatory requirements, intellectual property protection problems, and poor infrastructure for distribution and sales. Although drug companies have not invested heavily in NTDs, in several cases, rather than focus on profits, some have decided to donate key drugs to address NTDs. For example, Merck has had a program since the mid-1980s to donate ivermectin (Mectizan) indefinitely to support the global fight against onchocerciasis. GlaxoSmithKline and several other large pharmaceutical companies have donation programs as well. Drug donation, however, does not ameliorate the deficiency of new chemical entities being researched and developed. This is especially of concern with reports of emerging resistance among existing drugs. Governments, foundations, the non-profit sector, and the private sector have found new connections to help address market deficiencies by providing funding support and spreading both the costs and risks of NTD research and development. The proliferation of public–private partnerships (PPPs) has been recognized as a key innovation in the past decade, helping to unlock existing and new resources. [ citation needed ] Major PPPs for NTDs include: the Sabin Vaccine Institute , Norvartis Vaccines Institute for Global Health, MSD Wellcome Trust Hilleman Laboratories , Infectious Diseases Research Institute, Institut Pasteur and INSERM , WIPO Re:Search, and the International Vaccine Institute . Likewise, a number of new academic drug development centers have been created in recent years drawing in industry partners. Support for these centers is frequently traced to the Bill & Melinda Gates Foundation , the Sandler Foundation , and the Wellcome Trust . Growing NTD research and development capacity in middle-income countries is an area of policy interest. A 2009 study of biotechnology companies in India, China, Brazil, and South Africa revealed 62 NTD products in development and on the market out of approximately 500 products offered (~14%). When products to fight HIV, malaria, and TB were included in the analysis, the number increased to 123 products, approximately 25% of the total products offered. [ citation needed ] Researchers have argued that, unlike most multinationals, small and mid-sized "Global South" companies see significant business opportunities in the development of NTD-related diagnostics, biologics, pharmaceuticals, and services. Potential actions to improve and expand this R&D capacity have been recommended, including expansion of human capital, increased private investment, knowledge and patent sharing, infrastructure building for business incubation, and innovation support. [ citation needed ] Competitive innovation prizes have been used to spur development in a range of fields such as aerospace engineering, clean technology, and genomics. The X-Prize Foundation is launching a competition for high-speed, point-of-care diagnostics for tuberculosis. [ citation needed ] A more widely defined annual "Global Health EnterPrize" for neglected tropical diseases has been proposed to reward health innovators, particularly those based in countries where NTDs represent a serious health burden. [ citation needed ] The Bill & Melinda Gates Foundation offers the Grand Challenges Explorations Opportunities on a rolling basis. This grant program allows individuals from any organization or background to apply to address priority global health issues. Each project award is $100,000 and is drawn from a Foundation funding pool of $100 million. Awardees have tended to offer research projects on topics that are highly speculative but offer potentially game-changing breakthroughs in global health. [ citation needed ] In 2006, Ridley et al. recommended the development of a priority review voucher (PRV) in the journal Health Affairs . It gained interest from Senator Sam Brownback of Kansas, who championed its introduction in the FDA Amendments Act of 2007 . Under the enacted law, FDA approval of a non-NTD drug can be accelerated through the drug review process if paired with a drug that addresses an NTD. The potential economic benefit to a pharmaceutical company is estimated to be potentially as high as $300 million per drug. Three drugs have earned NTD PRVs to date (December 2014): Coartem (by Novartis, for malaria); bedaquiline (by Janssen, for TB); and miltefosine (by Knight, for leishmaniasis). However, the success of the PRV system is now under much scrutiny, given that Knight benefitted by $125 million from the sale of a PRV earned from a drug (miltefosine) that was largely researched and developed by the WHO. Médecins Sans Frontières are now pressuring Knight to guarantee to supply miltefosine at cost price, thus far without success. [ citation needed ] The PRV isn't limited to the pairing of drugs within a single company as it can be transferred between companies. Companies with NTD drug candidates in their pipelines but without a blockbuster drug are able to sell their vouchers, producing financial returns. In the EU, similar priority review incentives are now under consideration to increase the speed of regulatory pricing and reimbursement decisions. [ citation needed ] However, PRVs have been criticized as being open to manipulation and possibly encouraging errors through too rapid regulatory decision-making. Several companies and scientific organizations are participating in open-source initiatives to share drug data and patent information over the web, and facilitate virtual collaboration on NTD research. One rich area to explore is the wealth of genomic data resulting from the sequencing of parasite genomes. These data offer opportunities for the exploration of new therapeutic products using computational and open-source collaboration methods for drug discovery. The Tropical Disease Initiative, for example, has used large amounts of computing power to generate the protein structures for ten parasite genomes. An open-source drug bank was matched algorithmically to determine compounds with protein interaction activity, and two candidates were identified. In general, such methods may hold important opportunities for off-label use of existing approved drugs.In their 2002 review of the U.S. Food and Drug Administration (FDA) databases and the European Agency for the Evaluation of Medicinal Products , Troullier et al. found that 16 out of 1393 new chemical entities were approved for NTDs between 1975 and 1999 (~1%). Cohen et al. revisited the data and using the same methodology found 32 new chemical entities during the time period. In a second analysis using an expanded list of NTDs based on the G-FINDER survey, the number was slightly higher, with 46 new drugs and vaccines approved (~3% of the total including HIV drugs). Between 2000 and 2009, there has been some increase with an additional 26 newly approved drugs and vaccines for NTDs. A number of factors are recognized as contributing to the low number. The barrier most reported is the high cost of drug development. Estimates are that pharmaceutical companies' development costs to approval fall between $500 million and $2 billion. DiMasi, Hansen, and Grabowski calculated an average of $802 million in year 2000 dollars. Furthermore, the time that drugs are approved for use averages seven years out of the twenty years on patent, meaning a tendency for the market to focus on diseases of developed nations where high prices can be used to recoup research and development costs, and subsidize failed R&D efforts. In short, NTD research and development is considered a high investment risk, given that NTDs predominantly affect the poor in low- and middle-income countries. Additional barriers include drug safety regulatory requirements, intellectual property protection problems, and poor infrastructure for distribution and sales. Although drug companies have not invested heavily in NTDs, in several cases, rather than focus on profits, some have decided to donate key drugs to address NTDs. For example, Merck has had a program since the mid-1980s to donate ivermectin (Mectizan) indefinitely to support the global fight against onchocerciasis. GlaxoSmithKline and several other large pharmaceutical companies have donation programs as well. Drug donation, however, does not ameliorate the deficiency of new chemical entities being researched and developed. This is especially of concern with reports of emerging resistance among existing drugs. Governments, foundations, the non-profit sector, and the private sector have found new connections to help address market deficiencies by providing funding support and spreading both the costs and risks of NTD research and development. The proliferation of public–private partnerships (PPPs) has been recognized as a key innovation in the past decade, helping to unlock existing and new resources. [ citation needed ] Major PPPs for NTDs include: the Sabin Vaccine Institute , Norvartis Vaccines Institute for Global Health, MSD Wellcome Trust Hilleman Laboratories , Infectious Diseases Research Institute, Institut Pasteur and INSERM , WIPO Re:Search, and the International Vaccine Institute . Likewise, a number of new academic drug development centers have been created in recent years drawing in industry partners. Support for these centers is frequently traced to the Bill & Melinda Gates Foundation , the Sandler Foundation , and the Wellcome Trust . Growing NTD research and development capacity in middle-income countries is an area of policy interest. A 2009 study of biotechnology companies in India, China, Brazil, and South Africa revealed 62 NTD products in development and on the market out of approximately 500 products offered (~14%). When products to fight HIV, malaria, and TB were included in the analysis, the number increased to 123 products, approximately 25% of the total products offered. [ citation needed ] Researchers have argued that, unlike most multinationals, small and mid-sized "Global South" companies see significant business opportunities in the development of NTD-related diagnostics, biologics, pharmaceuticals, and services. Potential actions to improve and expand this R&D capacity have been recommended, including expansion of human capital, increased private investment, knowledge and patent sharing, infrastructure building for business incubation, and innovation support. [ citation needed ] Competitive innovation prizes have been used to spur development in a range of fields such as aerospace engineering, clean technology, and genomics. The X-Prize Foundation is launching a competition for high-speed, point-of-care diagnostics for tuberculosis. [ citation needed ] A more widely defined annual "Global Health EnterPrize" for neglected tropical diseases has been proposed to reward health innovators, particularly those based in countries where NTDs represent a serious health burden. [ citation needed ] The Bill & Melinda Gates Foundation offers the Grand Challenges Explorations Opportunities on a rolling basis. This grant program allows individuals from any organization or background to apply to address priority global health issues. Each project award is $100,000 and is drawn from a Foundation funding pool of $100 million. Awardees have tended to offer research projects on topics that are highly speculative but offer potentially game-changing breakthroughs in global health. [ citation needed ] In 2006, Ridley et al. recommended the development of a priority review voucher (PRV) in the journal Health Affairs . It gained interest from Senator Sam Brownback of Kansas, who championed its introduction in the FDA Amendments Act of 2007 . Under the enacted law, FDA approval of a non-NTD drug can be accelerated through the drug review process if paired with a drug that addresses an NTD. The potential economic benefit to a pharmaceutical company is estimated to be potentially as high as $300 million per drug. Three drugs have earned NTD PRVs to date (December 2014): Coartem (by Novartis, for malaria); bedaquiline (by Janssen, for TB); and miltefosine (by Knight, for leishmaniasis). However, the success of the PRV system is now under much scrutiny, given that Knight benefitted by $125 million from the sale of a PRV earned from a drug (miltefosine) that was largely researched and developed by the WHO. Médecins Sans Frontières are now pressuring Knight to guarantee to supply miltefosine at cost price, thus far without success. [ citation needed ] The PRV isn't limited to the pairing of drugs within a single company as it can be transferred between companies. Companies with NTD drug candidates in their pipelines but without a blockbuster drug are able to sell their vouchers, producing financial returns. In the EU, similar priority review incentives are now under consideration to increase the speed of regulatory pricing and reimbursement decisions. [ citation needed ] However, PRVs have been criticized as being open to manipulation and possibly encouraging errors through too rapid regulatory decision-making. Several companies and scientific organizations are participating in open-source initiatives to share drug data and patent information over the web, and facilitate virtual collaboration on NTD research. One rich area to explore is the wealth of genomic data resulting from the sequencing of parasite genomes. These data offer opportunities for the exploration of new therapeutic products using computational and open-source collaboration methods for drug discovery. The Tropical Disease Initiative, for example, has used large amounts of computing power to generate the protein structures for ten parasite genomes. An open-source drug bank was matched algorithmically to determine compounds with protein interaction activity, and two candidates were identified. In general, such methods may hold important opportunities for off-label use of existing approved drugs.Governments, foundations, the non-profit sector, and the private sector have found new connections to help address market deficiencies by providing funding support and spreading both the costs and risks of NTD research and development. The proliferation of public–private partnerships (PPPs) has been recognized as a key innovation in the past decade, helping to unlock existing and new resources. [ citation needed ] Major PPPs for NTDs include: the Sabin Vaccine Institute , Norvartis Vaccines Institute for Global Health, MSD Wellcome Trust Hilleman Laboratories , Infectious Diseases Research Institute, Institut Pasteur and INSERM , WIPO Re:Search, and the International Vaccine Institute . Likewise, a number of new academic drug development centers have been created in recent years drawing in industry partners. Support for these centers is frequently traced to the Bill & Melinda Gates Foundation , the Sandler Foundation , and the Wellcome Trust . Growing NTD research and development capacity in middle-income countries is an area of policy interest. A 2009 study of biotechnology companies in India, China, Brazil, and South Africa revealed 62 NTD products in development and on the market out of approximately 500 products offered (~14%). When products to fight HIV, malaria, and TB were included in the analysis, the number increased to 123 products, approximately 25% of the total products offered. [ citation needed ] Researchers have argued that, unlike most multinationals, small and mid-sized "Global South" companies see significant business opportunities in the development of NTD-related diagnostics, biologics, pharmaceuticals, and services. Potential actions to improve and expand this R&D capacity have been recommended, including expansion of human capital, increased private investment, knowledge and patent sharing, infrastructure building for business incubation, and innovation support. [ citation needed ]Competitive innovation prizes have been used to spur development in a range of fields such as aerospace engineering, clean technology, and genomics. The X-Prize Foundation is launching a competition for high-speed, point-of-care diagnostics for tuberculosis. [ citation needed ] A more widely defined annual "Global Health EnterPrize" for neglected tropical diseases has been proposed to reward health innovators, particularly those based in countries where NTDs represent a serious health burden. [ citation needed ] The Bill & Melinda Gates Foundation offers the Grand Challenges Explorations Opportunities on a rolling basis. This grant program allows individuals from any organization or background to apply to address priority global health issues. Each project award is $100,000 and is drawn from a Foundation funding pool of $100 million. Awardees have tended to offer research projects on topics that are highly speculative but offer potentially game-changing breakthroughs in global health. [ citation needed ]In 2006, Ridley et al. recommended the development of a priority review voucher (PRV) in the journal Health Affairs . It gained interest from Senator Sam Brownback of Kansas, who championed its introduction in the FDA Amendments Act of 2007 . Under the enacted law, FDA approval of a non-NTD drug can be accelerated through the drug review process if paired with a drug that addresses an NTD. The potential economic benefit to a pharmaceutical company is estimated to be potentially as high as $300 million per drug. Three drugs have earned NTD PRVs to date (December 2014): Coartem (by Novartis, for malaria); bedaquiline (by Janssen, for TB); and miltefosine (by Knight, for leishmaniasis). However, the success of the PRV system is now under much scrutiny, given that Knight benefitted by $125 million from the sale of a PRV earned from a drug (miltefosine) that was largely researched and developed by the WHO. Médecins Sans Frontières are now pressuring Knight to guarantee to supply miltefosine at cost price, thus far without success. [ citation needed ] The PRV isn't limited to the pairing of drugs within a single company as it can be transferred between companies. Companies with NTD drug candidates in their pipelines but without a blockbuster drug are able to sell their vouchers, producing financial returns. In the EU, similar priority review incentives are now under consideration to increase the speed of regulatory pricing and reimbursement decisions. [ citation needed ] However, PRVs have been criticized as being open to manipulation and possibly encouraging errors through too rapid regulatory decision-making. Several companies and scientific organizations are participating in open-source initiatives to share drug data and patent information over the web, and facilitate virtual collaboration on NTD research. One rich area to explore is the wealth of genomic data resulting from the sequencing of parasite genomes. These data offer opportunities for the exploration of new therapeutic products using computational and open-source collaboration methods for drug discovery. The Tropical Disease Initiative, for example, has used large amounts of computing power to generate the protein structures for ten parasite genomes. An open-source drug bank was matched algorithmically to determine compounds with protein interaction activity, and two candidates were identified. In general, such methods may hold important opportunities for off-label use of existing approved drugs.In 1977, Kenneth S. Warren , an American researcher, invented the concept of what is now "neglected tropical diseases". In 2005 Lorenzo Savioli , a senior United Nations civil servant, was appointed director of the "Department of Control of Neglected Tropical Diseases". The World Health Organization definition of neglected tropical disease has been criticised to be restrictive and described as a form of epistemic injustice, where conditions like snakebite are forced to be framed as a medical problem.

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Kolkata

Kolkata ( UK : / k ɒ l ˈ k ɑː t ə / or / k ɒ l ˈ k ʌ t ə / , US : / k oʊ l ˈ k ɑː t ɑː / , Bengali: [ kolˈkata ] ⓘ , IAST : Kōlkātā ; also known as Calcutta / k æ l ˈ k ʌ t ə / which was the official name until 2001 ) is the capital and largest city of the Indian state of West Bengal . It lies on the eastern bank of the Hooghly River , 80 km (50 mi) west of the border with Bangladesh . It is the primary financial and commercial centre of eastern and northeastern India . Kolkata is the seventh most populous city of India with an estimated city proper population of 4.5 million (0.45 crore). It is the centre of the Kolkata Metropolitan Region , one of the most populous metropolitan areas in the world with a population of over 15 million (1.5 crore) residents. Kolkata is the de facto cultural capital of India and a historically and culturally significant city in the historic region of Bengal . It is the second largest Bengali-speaking city in the world. It has the highest number of Nobel laureates among all cities in India. The three villages that predated Calcutta were ruled by the Nawab of Bengal under Mughal suzerainty . After the Nawab granted the East India Company a trading licence in 1690, the area was developed by the Company into Fort William . Nawab Siraj ud-Daulah occupied the fort in 1756 but was defeated at the Battle of Plassey in 1757, after his general Mir Jafar mutinied in support of the company, and was later made the Nawab for a brief time. Under company and later crown rule , Calcutta served as the de facto capital of India until 1911. Calcutta was the second largest city in the British Empire , after London , and was the centre of bureaucracy, politics, law, education, science and the arts in India. The city was associated with many of the figures and movements of the Bengali Renaissance . It was the hotbed of the Indian nationalist movement . The University of Calcutta and its affiliated colleges produced many leading figures of South Asia. Kolkata's architecture includes many imperial landmarks, including the Victoria Memorial , Howrah Bridge and the Grand Hotel . The city's heritage includes India's only Chinatown and remnants of Jewish , Armenian, Greek and Anglo-Indian communities. The city is closely linked with Bhadralok culture and the Zamindars of Bengal , including Bengali Hindu , Bengali Muslim and tribal aristocrats. The partition of Bengal affected the fortunes of the city. In the late 20th century, the city hosted the government-in-exile of Bangladesh during the Bangladesh Liberation War in 1971; it built India's first subway ; and it was overtaken by Mumbai (formerly Bombay) as India's largest city. The Port of Kolkata is India's oldest operating port. The city is often regarded as India's cultural capital. Following independence in 1947, Kolkata, which was once the premier centre of Indian commerce, culture, and politics, suffered many decades of political violence and economic stagnation before it rebounded. The city was also flooded with Hindu refugees from East Bengal (present-day Bangladesh) in the decades following the 1947 partition of India , transforming its landscape and shaping its politics. A demographically diverse city, the culture of Kolkata features idiosyncrasies that include distinctively close-knit neighbourhoods ( paras ) and freestyle conversations ( adda ). Kolkata is home to venerable institutions of national importance, including the Academy of Fine Arts , the Asiatic Society , the Indian Museum and the National Library of India . It is the centre of the Indian Bengali film industry, which is known as Tollywood . Among scientific institutions, Kolkata hosts the Geological Survey of India , the Botanical Survey of India , the Calcutta Mathematical Society , the Indian Science Congress Association , the Zoological Survey of India , the Horticultural Society , the Institution of Engineers , the Anthropological Survey of India and the Indian Public Health Association . Four Nobel laureates and two Nobel Memorial Prize winners are associated with the city. Though home to major cricketing venues and franchises, Kolkata stands out in India for being the country's centre of association football. Kolkata is known for its grand celebrations of the Hindu festival of Durga Puja , which is recognized by UNESCO for its importance to world heritage. Hence, Kolkata is also known as the 'City of Joy'. The word Kolkata ( Bengali : কলকাতা [ kolˈkata ] ) derives from Kôlikata ( Bengali: কলিকাতা [ ˈkɔliˌkata ] ), the Bengali language name of one of three villages that predated the arrival of the British; the other two villages were Sutanuti and Govindapur . There are several explanations for the etymology of this name: Although the city's name has always been pronounced Kolkata or Kôlikata in Bengali, the anglicised form Calcutta was the official name until 2001, when it was changed to Kolkata in order to match Bengali pronunciation. The discovery and archaeological study of Chandraketugarh , 35 km (22 mi) north of Kolkata, provide evidence that the region in which the city stands has been inhabited for over two millennia. Kolkata or Kalikata in its earliest mentions, is described to be a village surrounded with jungle on the bank of river Ganga as a renowned port, commercial hub and a hindu pilgrimage site for Kalighat Temple . The first mention of the Kalikata village was found in Bipradas Pipilai's Manasa Vijay (1495), where he describes how Chand Sadagar used to stop in Kalighat to worship Goddess Kali during in his path to trade voyage. Later Kalikata was also found to be mentioned in Mukundaram Chakrabarti 's Chandimangal (1594), Todar Mal's taxation-list in 1596 and Krishnaram Das's Kalikamangal (1676-77). Kolkata's recorded history began in 1690 with the arrival of the English East India Company , which was consolidating its trade business in Bengal. Job Charnock is often regarded as the founder of the city; however, in response to a public petition, the Calcutta High Court ruled in 2003 that the city does not have a founder. The area occupied by the present-day city encompassed three villages: Kalikata , Gobindapur and Sutanuti . Kalikata was a fishing village; Sutanuti was a riverside weavers' village; and Gobindapur was a trading post for Indian merchant princes. These villages were part of an estate belonging to the Sabarna Roy Choudhury family of zamindars . The estate was sold to the East India Company in 1698. : 1 In 1712, the British completed the construction of Fort William , located on the east bank of the Hooghly River to protect their trading factory. Facing frequent skirmishes with French forces , the British began to upgrade their fortifications in 1756. The Nawab of Bengal, Siraj-ud-Daulah , condemned the militarisation and tax evasion by the company. His warning went unheeded, and the Nawab attacked; his capture of Fort William led to the killings of several East India company officials in the Black Hole of Calcutta . A force of Company soldiers ( sepoys ) and British troops led by Robert Clive recaptured the city the following year. Per the 1765 Treaty of Allahabad following the battle of Buxar , East India company was appointed imperial tax collector of the Mughal emperor in the province of Bengal, Bihar and Orissa, while Mughal-appointed Nawabs continued to rule the province. Declared a presidency city , Calcutta became the headquarters of the East India Company by 1773. In 1793, ruling power of the Nawabs were abolished, and East India company took complete control of the city and the province. In the early 19th century, the marshes surrounding the city were drained; the government area was laid out along the banks of the Hooghly River. Richard Wellesley , Governor-General of the Presidency of Fort William between 1797 and 1805, was largely responsible for the development of the city and its public architecture. Throughout the late 18th and 19th century, the city was a centre of the East India Company's opium trade. A census in 1837 records the population of the city proper as 229,700, of which the British residents made up only 3,138. The same source says another 177,000 resided in the suburbs and neighbouring villages, making the entire population of greater Calcutta 406,700. In 1864, a typhoon struck the city and killed about 60,000 in Kolkata. By the 1850s, Calcutta had two areas: White Town, which was primarily British and centred on Chowringhee and Dalhousie Square ; and Black Town, mainly Indian and centred on North Calcutta. The city underwent rapid industrial growth starting in the early 1850s, especially in the textile and jute industries; this encouraged British companies to massively invest in infrastructure projects, which included telegraph connections and Howrah railway station . The coalescence of British and Indian culture resulted in the emergence of a new babu class of urbane Indians, whose members were often bureaucrats, professionals, newspaper readers, and Anglophiles; they usually belonged to upper-caste Hindu communities. In the 19th century, the Bengal Renaissance brought about an increased sociocultural sophistication among city denizens. In 1883, Calcutta was host to the first national conference of the Indian National Association , which was the first avowed nationalist organisation in India. The partition of Bengal in 1905 along religious lines led to mass protests, making Calcutta a less hospitable place for the British. The capital was moved to New Delhi in 1911. Calcutta continued to be a centre for revolutionary organisations associated with the Indian independence movement . The city and its port were bombed several times by the Japanese between 1942 and 1944, during World War II . Millions starved to death during the Bengal famine of 1943 (at the same time of the war) due to a combination of military, administrative, and natural factors. Demands for the creation of a Muslim state led in 1946 to an episode of communal violence that killed over 4,000. The partition of India led to further clashes and a demographic shift—many Muslims left for East Pakistan (present day Bangladesh ), while hundreds of thousands of Hindus fled into the city. During the 1960s and 1970s, severe power shortages, strikes and a violent Marxist – Maoist movement by groups known as the Naxalites damaged much of the city's infrastructure, resulting in economic stagnation. During East Pakistan's secessionist war of independence in 1971, the city was home to the government-in-exile of Bangladesh . During the war, refugees poured into West Bengal and strained Kolkata's infrastructure. The Eastern Command of the Indian military, which is based in Fort William, played a pivotal role in the Indo-Pakistani War of 1971 and securing the surrender of Pakistan . During the mid-1980s, Mumbai (then called Bombay) overtook Kolkata as India's most populous city. In 1985, Prime Minister Rajiv Gandhi dubbed Kolkata a "dying city" in light of its socio-political woes. In the period 1977–2011, West Bengal was governed from Kolkata by the Left Front , which was dominated by the Communist Party of India (CPM). It was the world's longest-serving democratically elected communist government, during which Kolkata was a key base for Indian communism . In the 2011 West Bengal Legislative Assembly election , Left Front was defeated by the Trinamool Congress . The city's economic recovery gathered momentum after the 1990s, when India began to institute pro-market reforms . Since 2000, the information technology (IT) services sector has revitalised Kolkata's stagnant economy. The city is also experiencing marked growth in its manufacturing base. Spread roughly north–south along the east bank of the Hooghly River , Kolkata sits within the lower Ganges Delta of eastern India approximately 75 km (47 mi) west of the international border with Bangladesh; the city's elevation is 1.5–9 m (5–30 ft) . Much of the city was originally a wetland that was reclaimed over the decades to accommodate a burgeoning population. The remaining undeveloped areas, known as the East Kolkata Wetlands , were designated a "wetland of international importance" by the Ramsar Convention (1975). As with most of the Indo-Gangetic Plain , the soil and water are predominantly alluvial in origin. Kolkata is located over the "Bengal basin", a pericratonic tertiary basin. Bengal basin comprises three structural units: shelf or platform in the west; central hinge or shelf/slope break; and deep basinal part in the east and southeast. Kolkata is located atop the western part of the hinge zone which is about 25 km (16 mi) wide at a depth of about 45,000 m (148,000 ft) below the surface. The shelf and hinge zones have many faults, among them some are active. Total thickness of sediment below Kolkata is nearly 7,500 m (24,600 ft) above the crystalline basement ; of these the top 350–450 m (1,150–1,480 ft) is Quaternary , followed by 4,500–5,500 m (14,760–18,040 ft) of Tertiary sediments, 500–700 m (1,640–2,300 ft) trap wash of Cretaceous trap and 600–800 m (1,970–2,620 ft) Permian - Carboniferous Gondwana rocks. The quaternary sediments consist of clay, silt and several grades of sand and gravel. These sediments are sandwiched between two clay beds: the lower one at a depth of 250–650 m (820–2,130 ft) ; the upper one 10–40 m (30–130 ft) in thickness. According to the Bureau of Indian Standards , on a scale ranging from I to V in order of increasing susceptibility to earthquakes, the city lies inside seismic zone III . Kolkata is subject to a tropical wet-and-dry climate that is designated Aw under the Köppen climate classification . According to a United Nations Development Programme report, its wind and cyclone zone is "very high damage risk". The annual mean temperature is 26.8 °C (80.2 °F) ; monthly mean temperatures are 19–30 °C (66–86 °F) . Summers (March–June) are hot and humid, with temperatures in the low 30s Celsius; during dry spells, maximum temperatures sometime exceed 40 °C (104 °F) in May and June. Winter lasts for roughly 2 + 1 ⁄ 2 months, with seasonal lows dipping to 9–11 °C (48–52 °F) in December and January. May is the hottest month, with daily temperatures ranging from 27–37 °C (81–99 °F) ; January, the coldest month, has temperatures varying from 12–23 °C (54–73 °F) . The highest recorded temperature is 43.9 °C (111.0 °F) , and the lowest is 5 °C (41 °F) . The winter is mild and very comfortable weather pertains over the city throughout this season. Often, in April–June, the city is struck by heavy rains or dusty squalls that are followed by thunderstorms or hailstorms, bringing cooling relief from the prevailing humidity. These thunderstorms are convective in nature, and are known locally as kal bôishakhi ( কালবৈশাখী ), or "Nor'westers" in English. Rains brought by the Bay of Bengal branch of the south-west summer monsoon lash Kolkata between June and September, supplying it with most of its annual rainfall of about 1,850 mm (73 in) . The highest monthly rainfall total occurs in July and August. In these months often incessant rain for days brings life to a stall for the city dwellers. The city receives 2,107 hours of sunshine per year, with maximum sunlight exposure occurring in April. Kolkata has been hit by several cyclones; these include systems occurring in 1737 and 1864 that killed thousands. More recently, Cyclone Aila in 2009 and Cyclone Amphan in 2020 caused widespread damage to Kolkata by bringing catastrophic winds and torrential rainfall. Pollution is a major concern in Kolkata. As of 2008 [ update ] , sulphur dioxide and nitrogen dioxide annual concentration were within the national ambient air quality standards of India, but respirable suspended particulate matter levels were high, and on an increasing trend for five consecutive years, causing smog and haze. Severe air pollution in the city has caused a rise in pollution-related respiratory ailments, such as lung cancer. Kolkata is subject to a tropical wet-and-dry climate that is designated Aw under the Köppen climate classification . According to a United Nations Development Programme report, its wind and cyclone zone is "very high damage risk". The annual mean temperature is 26.8 °C (80.2 °F) ; monthly mean temperatures are 19–30 °C (66–86 °F) . Summers (March–June) are hot and humid, with temperatures in the low 30s Celsius; during dry spells, maximum temperatures sometime exceed 40 °C (104 °F) in May and June. Winter lasts for roughly 2 + 1 ⁄ 2 months, with seasonal lows dipping to 9–11 °C (48–52 °F) in December and January. May is the hottest month, with daily temperatures ranging from 27–37 °C (81–99 °F) ; January, the coldest month, has temperatures varying from 12–23 °C (54–73 °F) . The highest recorded temperature is 43.9 °C (111.0 °F) , and the lowest is 5 °C (41 °F) . The winter is mild and very comfortable weather pertains over the city throughout this season. Often, in April–June, the city is struck by heavy rains or dusty squalls that are followed by thunderstorms or hailstorms, bringing cooling relief from the prevailing humidity. These thunderstorms are convective in nature, and are known locally as kal bôishakhi ( কালবৈশাখী ), or "Nor'westers" in English. Rains brought by the Bay of Bengal branch of the south-west summer monsoon lash Kolkata between June and September, supplying it with most of its annual rainfall of about 1,850 mm (73 in) . The highest monthly rainfall total occurs in July and August. In these months often incessant rain for days brings life to a stall for the city dwellers. The city receives 2,107 hours of sunshine per year, with maximum sunlight exposure occurring in April. Kolkata has been hit by several cyclones; these include systems occurring in 1737 and 1864 that killed thousands. More recently, Cyclone Aila in 2009 and Cyclone Amphan in 2020 caused widespread damage to Kolkata by bringing catastrophic winds and torrential rainfall.The annual mean temperature is 26.8 °C (80.2 °F) ; monthly mean temperatures are 19–30 °C (66–86 °F) . Summers (March–June) are hot and humid, with temperatures in the low 30s Celsius; during dry spells, maximum temperatures sometime exceed 40 °C (104 °F) in May and June. Winter lasts for roughly 2 + 1 ⁄ 2 months, with seasonal lows dipping to 9–11 °C (48–52 °F) in December and January. May is the hottest month, with daily temperatures ranging from 27–37 °C (81–99 °F) ; January, the coldest month, has temperatures varying from 12–23 °C (54–73 °F) . The highest recorded temperature is 43.9 °C (111.0 °F) , and the lowest is 5 °C (41 °F) . The winter is mild and very comfortable weather pertains over the city throughout this season. Often, in April–June, the city is struck by heavy rains or dusty squalls that are followed by thunderstorms or hailstorms, bringing cooling relief from the prevailing humidity. These thunderstorms are convective in nature, and are known locally as kal bôishakhi ( কালবৈশাখী ), or "Nor'westers" in English. Rains brought by the Bay of Bengal branch of the south-west summer monsoon lash Kolkata between June and September, supplying it with most of its annual rainfall of about 1,850 mm (73 in) . The highest monthly rainfall total occurs in July and August. In these months often incessant rain for days brings life to a stall for the city dwellers. The city receives 2,107 hours of sunshine per year, with maximum sunlight exposure occurring in April. Kolkata has been hit by several cyclones; these include systems occurring in 1737 and 1864 that killed thousands. More recently, Cyclone Aila in 2009 and Cyclone Amphan in 2020 caused widespread damage to Kolkata by bringing catastrophic winds and torrential rainfall.Pollution is a major concern in Kolkata. As of 2008 [ update ] , sulphur dioxide and nitrogen dioxide annual concentration were within the national ambient air quality standards of India, but respirable suspended particulate matter levels were high, and on an increasing trend for five consecutive years, causing smog and haze. Severe air pollution in the city has caused a rise in pollution-related respiratory ailments, such as lung cancer. Kolkata, which is under the jurisdiction of the Kolkata Municipal Corporation (KMC), has an area of 206.08 km 2 (80 sq mi) . The east–west dimension of the city is comparatively narrow, stretching from the Hooghly River in the west to roughly the Eastern Metropolitan Bypass in the east—a span of 9–10 km (5.6–6.2 mi) . The north–south distance is greater, and its axis is used to section the city into North, Central, South and East Kolkata. North Kolkata is the oldest part of the city. Characterised by 19th-century architecture and narrow alleyways, it includes areas such as Jorasanko , Rajabazar , Maniktala , Ultadanga , Shyambazar , Shobhabazar , Bagbazar , Cossipore , Sinthee etc. The north suburban areas like Dum Dum , Baranagar , Belgharia , Sodepur , Khardaha , New Barrackpore , Madhyamgram , Barrackpore , Barasat etc. are also within the city of Kolkata (as a metropolitan structure). : 65–66 Central Kolkata hosts the central business district. It contains B. B. D. Bagh , formerly known as Dalhousie Square, and the Esplanade on its east; Rajiv Gandhi Sarani is on its west. The West Bengal Secretariat , General Post Office , Reserve Bank of India , Calcutta High Court , Lalbazar Police Headquarters and several other government and private offices are located there. Another business hub is the area south of Park Street , which comprises thoroughfares such as Jawahar Lal Nehru Road , Abanindra Nath Tagore Sarani , Dr. Martin Luther King Sarani, Dr. Upendra Nath Brahmachari Sarani, Shakespeare Sarani and Acharay Jagadish Chandra Basu Road . South Kolkata developed after India gained independence in 1947; it includes upscale neighbourhoods such as Bhowanipore , Alipore , Ballygunge , Kasba , Dhakuria , Santoshpur , Garia , Golf Green , Tollygunge , New Alipore , Behala , Barisha etc. The south suburban areas like Maheshtala , Budge Budge , Rajpur Sonarpur , Baruipur etc. are also within the city of Kolkata (as a metropolitan structure). The Maidan is a large open field in the heart of the city that has been called the "lungs of Kolkata" and accommodates sporting events and public meetings. The Victoria Memorial and Kolkata Race Course are located at the southern end of the Maidan. Among the other parks are Central Park in Bidhannagar and Millennium Park on Rajiv Gandhi Sarani, along the Hooghly River. The Kolkata metropolitan area is spread over 1,886.67 km 2 (728.45 sq mi) : 7 and comprises 4 municipal corporations (including Kolkata Municipal Corporation), 37 local municipalities and 24 panchayat samitis , as of 2011. : 7 The urban agglomeration encompassed 72 cities and 527 towns and villages, as of 2006. Suburban areas in the Kolkata metropolitan area incorporate parts of the following districts: North 24 Parganas , South 24 Parganas , Howrah , Hooghly and Nadia . : 15 Two planned townships in the greater Kolkata region are Bidhannagar , also known as Salt Lake City and located north-east of the city; and Rajarhat , also called New Town and located east of Bidhannagar. In the 2000s, Sector 5 in Bidhannagar developed into a business hub for information technology and telecommunication companies. Both Bidhannagar and New Town are situated outside the Kolkata Municipal Corporation limits, in their own municipalities. Kolkata, which is under the jurisdiction of the Kolkata Municipal Corporation (KMC), has an area of 206.08 km 2 (80 sq mi) . The east–west dimension of the city is comparatively narrow, stretching from the Hooghly River in the west to roughly the Eastern Metropolitan Bypass in the east—a span of 9–10 km (5.6–6.2 mi) . The north–south distance is greater, and its axis is used to section the city into North, Central, South and East Kolkata. North Kolkata is the oldest part of the city. Characterised by 19th-century architecture and narrow alleyways, it includes areas such as Jorasanko , Rajabazar , Maniktala , Ultadanga , Shyambazar , Shobhabazar , Bagbazar , Cossipore , Sinthee etc. The north suburban areas like Dum Dum , Baranagar , Belgharia , Sodepur , Khardaha , New Barrackpore , Madhyamgram , Barrackpore , Barasat etc. are also within the city of Kolkata (as a metropolitan structure). : 65–66 Central Kolkata hosts the central business district. It contains B. B. D. Bagh , formerly known as Dalhousie Square, and the Esplanade on its east; Rajiv Gandhi Sarani is on its west. The West Bengal Secretariat , General Post Office , Reserve Bank of India , Calcutta High Court , Lalbazar Police Headquarters and several other government and private offices are located there. Another business hub is the area south of Park Street , which comprises thoroughfares such as Jawahar Lal Nehru Road , Abanindra Nath Tagore Sarani , Dr. Martin Luther King Sarani, Dr. Upendra Nath Brahmachari Sarani, Shakespeare Sarani and Acharay Jagadish Chandra Basu Road . South Kolkata developed after India gained independence in 1947; it includes upscale neighbourhoods such as Bhowanipore , Alipore , Ballygunge , Kasba , Dhakuria , Santoshpur , Garia , Golf Green , Tollygunge , New Alipore , Behala , Barisha etc. The south suburban areas like Maheshtala , Budge Budge , Rajpur Sonarpur , Baruipur etc. are also within the city of Kolkata (as a metropolitan structure). The Maidan is a large open field in the heart of the city that has been called the "lungs of Kolkata" and accommodates sporting events and public meetings. The Victoria Memorial and Kolkata Race Course are located at the southern end of the Maidan. Among the other parks are Central Park in Bidhannagar and Millennium Park on Rajiv Gandhi Sarani, along the Hooghly River.The Kolkata metropolitan area is spread over 1,886.67 km 2 (728.45 sq mi) : 7 and comprises 4 municipal corporations (including Kolkata Municipal Corporation), 37 local municipalities and 24 panchayat samitis , as of 2011. : 7 The urban agglomeration encompassed 72 cities and 527 towns and villages, as of 2006. Suburban areas in the Kolkata metropolitan area incorporate parts of the following districts: North 24 Parganas , South 24 Parganas , Howrah , Hooghly and Nadia . : 15 Two planned townships in the greater Kolkata region are Bidhannagar , also known as Salt Lake City and located north-east of the city; and Rajarhat , also called New Town and located east of Bidhannagar. In the 2000s, Sector 5 in Bidhannagar developed into a business hub for information technology and telecommunication companies. Both Bidhannagar and New Town are situated outside the Kolkata Municipal Corporation limits, in their own municipalities. Kolkata is the commercial and financial hub of East and North-East India and home to the Calcutta Stock Exchange . It is a major commercial and military port, and is one of five cities in eastern India (alongside Bhubaneswar , Guwahati , Imphal , and Kushinagar ) to have an international airport. Once India's leading city, Kolkata experienced a steady economic decline in the decades following India's independence due to steep population increases and a rise in militant trade-unionism , which included frequent strikes that were backed by left-wing parties. From the 1960s to the late 1990s, several factories were closed and businesses relocated. The lack of capital and resources added to the depressed state of the city's economy and gave rise to an unwelcome sobriquet: the "dying city". The city's fortunes improved after the Indian economy was liberalised in the 1990s and changes in economic policy were enacted by the West Bengal state government. Recent estimates of the economy of Kolkata's metropolitan area have ranged from $150 to $250 billion ( PPP GDP), and have ranked it third-most productive metro area of India. Flexible production has been the norm in Kolkata, which has an informal sector that employs more than 40% of the labour force. One unorganised group, roadside hawkers , generated business worth ₹ 87.72 billion ( US$ 2 billion) in 2005. As of 2001 [ update ] , around 0.81% of the city's workforce was employed in the primary sector (agriculture, forestry, mining, etc.); 15.49% worked in the secondary sector (industrial and manufacturing); and 83.69% worked in the tertiary sector (service industries). : 19 As of 2003 [ update ] , the majority of households in slums were engaged in occupations belonging to the informal sector; 36.5% were involved in servicing the urban middle class (as maids, drivers, etc.) and 22.2% were casual labourers . : 11 About 34% of the available labour force in Kolkata slums were unemployed. : 11 According to one estimate, almost a quarter of the population live on less than 27 rupees (equivalent to 45 US cents) per day. Major manufacturing companies in the city are Alstom , Larsen & Toubro , Fosroc , Videocon . As in many other Indian cities, information technology became a high-growth sector in Kolkata starting in the late 1990s; the city's IT sector grew at 70% per annum—a rate that was twice the national average. The 2000s saw a surge of investments in the real estate, infrastructure, retail, and hospitality sectors; several large shopping malls and hotels were launched. Companies such as ITC Limited , CESC Limited , Exide Industries , Emami , Eveready Industries India , Lux Industries , Rupa Company , Berger Paints , Birla Corporation , Britannia Industries and Purushottam Publishers are headquartered in the city. Philips India, PricewaterhouseCoopers India, Tata Global Beverages , and Tata Steel have their registered office and zonal headquarters in Kolkata. Kolkata hosts the headquarters of two major banks: UCO Bank , and Bandhan Bank . Reserve Bank of India , State Bank of India have its eastern zonal office in Kolkata. India Government Mint, Kolkata is one of the four mints in India. Some of the oldest public sector companies are headquartered in the city such as the Coal India Limited , National Insurance Company , Garden Reach Shipbuilders & Engineers , Tea Board of India , Geological Survey of India , Zoological Survey of India , Botanical Survey of India , Jute Corporation of India , National Test House, Hindustan Copper and the Ordnance Factories Board of the Indian Ministry of Defence .The demonym for residents of Kolkata are Calcuttan and Kolkatan . According to provisional results of the 2011 national census, Kolkata district, which occupies an area of 185 km 2 (71 sq mi) , had a population of 4,486,679; its population density was 24,252/km 2 (62,810/sq mi) . This represents a decline of 1.88% during the decade 2001–11. The sex ratio is 899 females per 1000 males—lower than the national average. The ratio is depressed by the influx of working males from surrounding rural areas, from the rest of West Bengal; these men commonly leave their families behind. Kolkata's literacy rate of 87.14% exceeds the national average of 74%. The final population totals of census 2011 stated the population of city as 4,496,694. The urban agglomeration had a population of 14,112,536 in 2011. As of 2003 [ update ] , about one-third of the population, or 15 lakh (1.5 million) people, lived in 3,500 unregistered squatter-occupied and 2,011 registered slums . : 4 : 92 The authorised slums (with access to basic services like water, latrines, trash removal by the Kolkata Municipal Corporation) can be broadly divided into two groups— bustees , in which slum dwellers have some long term tenancy agreement with the landowners; and udbastu colonies , settlements which had been leased to refugees from present-day Bangladesh by the government. : 5 The unauthorised slums (devoid of basic services provided by the municipality) are occupied by squatters who started living on encroached lands—mainly along canals, railway lines and roads. : 92 : 5 According to the 2005 National Family Health Survey, around 14% of the households in Kolkata were poor, while 33% lived in slums, indicating a substantial proportion of households in slum areas were better off economically than the bottom quarter of urban households in terms of wealth status. : 23 Mother Teresa was awarded the Nobel Peace Prize for founding and working with the Missionaries of Charity in Kolkata—an organisation "whose primary task was to love and care for those persons nobody was prepared to look after". Languages spoken in Kolkata city (2011 census) Bengali , the official state language, is the dominant language in Kolkata. English is also used, particularly by the white-collar workforce. Hindi and Urdu are spoken by a sizeable minority. Bengali Hindus form the majority of Kolkata's population; Marwaris , Biharis and Urdu-speaking Muslims compose large minorities. Among Kolkata's smaller communities are Chinese , Tamils , Nepalis , Pathans/Afghans (locally known as Kabuliwala ) Odias , Telugus , Gujaratis , Anglo-Indians , Armenians , Bengali Muslims , Greeks , Tibetans , Maharashtrians , Konkanis , Malayalees , Punjabis and Parsis . : 3 The number of Armenians, Greeks, Jews and other foreign-origin groups declined during the 20th century. The Jewish population of Kolkata was 5,000 during World War II, but declined after Indian independence and the establishment of Israel; by 2013, there were 25 Jews in the city. India's sole Chinatown is in eastern Kolkata; once home to 20,000 ethnic Chinese, its population dropped to around 2,000 as of 2009 [ update ] as a result of multiple factors including repatriation and denial of Indian citizenship following the 1962 Sino-Indian War , and immigration to foreign countries for better economic opportunities. The Chinese community traditionally worked in the local tanning industry and ran Chinese restaurants. According to the 2011 census, 76.51% of the population is Hindu , 20.60% Muslim , 0.88% Christian and 0.47% Jain . The remainder of the population includes Sikhs , Buddhists , and other religions which accounts for 0.45% of the population; 1.09% did not state a religion in the census. Kolkata reported 67.6% of Special and Local Laws crimes registered in 35 large Indian cities during 2004. The demonym for residents of Kolkata are Calcuttan and Kolkatan . According to provisional results of the 2011 national census, Kolkata district, which occupies an area of 185 km 2 (71 sq mi) , had a population of 4,486,679; its population density was 24,252/km 2 (62,810/sq mi) . This represents a decline of 1.88% during the decade 2001–11. The sex ratio is 899 females per 1000 males—lower than the national average. The ratio is depressed by the influx of working males from surrounding rural areas, from the rest of West Bengal; these men commonly leave their families behind. Kolkata's literacy rate of 87.14% exceeds the national average of 74%. The final population totals of census 2011 stated the population of city as 4,496,694. The urban agglomeration had a population of 14,112,536 in 2011. As of 2003 [ update ] , about one-third of the population, or 15 lakh (1.5 million) people, lived in 3,500 unregistered squatter-occupied and 2,011 registered slums . : 4 : 92 The authorised slums (with access to basic services like water, latrines, trash removal by the Kolkata Municipal Corporation) can be broadly divided into two groups— bustees , in which slum dwellers have some long term tenancy agreement with the landowners; and udbastu colonies , settlements which had been leased to refugees from present-day Bangladesh by the government. : 5 The unauthorised slums (devoid of basic services provided by the municipality) are occupied by squatters who started living on encroached lands—mainly along canals, railway lines and roads. : 92 : 5 According to the 2005 National Family Health Survey, around 14% of the households in Kolkata were poor, while 33% lived in slums, indicating a substantial proportion of households in slum areas were better off economically than the bottom quarter of urban households in terms of wealth status. : 23 Mother Teresa was awarded the Nobel Peace Prize for founding and working with the Missionaries of Charity in Kolkata—an organisation "whose primary task was to love and care for those persons nobody was prepared to look after". Languages spoken in Kolkata city (2011 census) Bengali , the official state language, is the dominant language in Kolkata. English is also used, particularly by the white-collar workforce. Hindi and Urdu are spoken by a sizeable minority. Bengali Hindus form the majority of Kolkata's population; Marwaris , Biharis and Urdu-speaking Muslims compose large minorities. Among Kolkata's smaller communities are Chinese , Tamils , Nepalis , Pathans/Afghans (locally known as Kabuliwala ) Odias , Telugus , Gujaratis , Anglo-Indians , Armenians , Bengali Muslims , Greeks , Tibetans , Maharashtrians , Konkanis , Malayalees , Punjabis and Parsis . : 3 The number of Armenians, Greeks, Jews and other foreign-origin groups declined during the 20th century. The Jewish population of Kolkata was 5,000 during World War II, but declined after Indian independence and the establishment of Israel; by 2013, there were 25 Jews in the city. India's sole Chinatown is in eastern Kolkata; once home to 20,000 ethnic Chinese, its population dropped to around 2,000 as of 2009 [ update ] as a result of multiple factors including repatriation and denial of Indian citizenship following the 1962 Sino-Indian War , and immigration to foreign countries for better economic opportunities. The Chinese community traditionally worked in the local tanning industry and ran Chinese restaurants. According to the 2011 census, 76.51% of the population is Hindu , 20.60% Muslim , 0.88% Christian and 0.47% Jain . The remainder of the population includes Sikhs , Buddhists , and other religions which accounts for 0.45% of the population; 1.09% did not state a religion in the census. Kolkata reported 67.6% of Special and Local Laws crimes registered in 35 large Indian cities during 2004. Kolkata is administered by several government agencies. The Kolkata Municipal Corporation , or KMC, oversees and manages the civic infrastructure of the city's 16 boroughs, which together encompass 144 wards. Each ward elects a councillor to the KMC. Each borough has a committee of councillors, each of whom is elected to represent a ward. By means of the borough committees, the corporation undertakes urban planning and maintains roads, government-aided schools, hospitals, and municipal markets. As Kolkata's apex body, the corporation discharges its functions through the mayor-in-council, which comprises a mayor , a deputy mayor, and ten other elected members of the KMC. The functions of the KMC include water supply, drainage and sewerage, sanitation, solid waste management, street lighting, and building regulation. Kolkata's administrative agencies have areas of jurisdiction that do not coincide. Listed in ascending order by area, they are: Kolkata district ; the Kolkata Police area and the Kolkata Municipal Corporation area, or "Kolkata city"; and the Kolkata metropolitan area , which is the city's urban agglomeration. The agency overseeing the latter, the Kolkata Metropolitan Development Authority , is responsible for the statutory planning and development of greater Kolkata. The Kolkata Municipal Corporation was ranked first out of 21 cities for best governance and administrative practices in India in 2014. It scored 4.0 on 10 compared to the national average of 3.3. The Kolkata Port Trust, an agency of the central government, manages the city's river port. As of 2023 [ update ] , the All India Trinamool Congress controls the KMC; the mayor is Firhad Hakim , while the deputy mayor is Atin Ghosh. The city has an apolitical titular post, that of the Sheriff of Kolkata , which presides over various city-related functions and conferences. As the seat of the Government of West Bengal , Kolkata is home to not only the offices of the local governing agencies, but also the West Bengal Legislative Assembly ; the state secretariat, which is housed in the Writers' Building; and the Calcutta High Court . Most government establishments and institutions are housed in the centre of the city in B. B. D. Bagh (formerly known as Dalhousie Square). The Calcutta High Court is the oldest High Court in India. It was preceded by the Supreme Court of Judicature at Fort William which was established in 1774. The Calcutta High Court has jurisdiction over the state of West Bengal and the Union Territory of the Andaman and Nicobar Islands . Kolkata has lower courts: the Court of Small Causes and the City Civil Court decide civil matters; the Sessions Court rules in criminal cases. The Kolkata Police , headed by a police commissioner, is overseen by the West Bengal Ministry of Home Affairs . The Kolkata district elects two representatives to India's lower house, the Lok Sabha , and 11 representatives to the state legislative assembly. The Kolkata police district registered 15,510 Indian Penal Code cases in 2010, the 8th-highest total in the country. In 2010, the crime rate was 117.3 per 100,000, below the national rate of 187.6; it was the lowest rate among India's largest cities. The Kolkata Municipal Corporation supplies the city with potable water that is sourced from the Hooghly River; most of it is treated and purified at the Palta pumping station located in North 24 Parganas district. [ failed verification ] Roughly 95% of the 4,000 tonnes of refuse produced daily by the city is transported to the dumping grounds in Dhapa , which is east of the town. To promote the recycling of garbage and sewer water, agriculture is encouraged on the dumping grounds. Parts of the city lack proper sewerage, leading to unsanitary methods of waste disposal. In 1856, the Bengal Government appointed George Turnbull to be the Commissioner of Drainage and Sewerage to improve the city's sewerage. Turnbull's main job was to be the Chief Engineer of the East Indian Railway Company responsible for building the first railway 541 miles (871 km) from Howrah to Varanasi (then Benares ). Electricity is supplied by the privately operated Calcutta Electric Supply Corporation , or CESC, to the city proper; the West Bengal State Electricity Board supplies it in the suburbs. Fire services are handled by the West Bengal Fire Service , a state agency. As of 2012 [ update ] , the city had 16 fire stations. State-owned Bharat Sanchar Nigam Limited , or BSNL, as well as private enterprises, among them Vodafone Idea , Bharti Airtel , Reliance Jio are the leading telephone and cell phone service providers in the city. : 25–26 : 179 with Kolkata being the first city in India to have cell phone and 4G connectivity, the GSM and CDMA cellular coverage is extensive. As of 2010 [ update ] , Kolkata has 7 percent of the total broadband internet consumers in India; BSNL, VSNL, Tata Indicom, Sify, Hathway, Airtel, and Jio are among the main vendors. The Eastern Command of the Indian Army is based in the city. Being one of India's major city and the largest city in eastern and north-eastern India, Kolkata hosts diplomatic missions of many countries such as Australia, Bangladesh, Bhutan, Canada, People's Republic of China, France, Germany, Italy, Japan, Myanmar, Nepal, Russia, Sri Lanka, Switzerland, Thailand, United Kingdom and United States . The U.S Consulate in Kolkata is the US Department of State 's second-oldest Consulate and dates from 19 November 1792. The Diplomatic representation of more than 65 Countries and International Organization is present in Kolkata as Consulate office, honorary Consulate office, Cultural Centre, Deputy High Commission and Economic section and Trade Representation office. Kolkata is administered by several government agencies. The Kolkata Municipal Corporation , or KMC, oversees and manages the civic infrastructure of the city's 16 boroughs, which together encompass 144 wards. Each ward elects a councillor to the KMC. Each borough has a committee of councillors, each of whom is elected to represent a ward. By means of the borough committees, the corporation undertakes urban planning and maintains roads, government-aided schools, hospitals, and municipal markets. As Kolkata's apex body, the corporation discharges its functions through the mayor-in-council, which comprises a mayor , a deputy mayor, and ten other elected members of the KMC. The functions of the KMC include water supply, drainage and sewerage, sanitation, solid waste management, street lighting, and building regulation. Kolkata's administrative agencies have areas of jurisdiction that do not coincide. Listed in ascending order by area, they are: Kolkata district ; the Kolkata Police area and the Kolkata Municipal Corporation area, or "Kolkata city"; and the Kolkata metropolitan area , which is the city's urban agglomeration. The agency overseeing the latter, the Kolkata Metropolitan Development Authority , is responsible for the statutory planning and development of greater Kolkata. The Kolkata Municipal Corporation was ranked first out of 21 cities for best governance and administrative practices in India in 2014. It scored 4.0 on 10 compared to the national average of 3.3. The Kolkata Port Trust, an agency of the central government, manages the city's river port. As of 2023 [ update ] , the All India Trinamool Congress controls the KMC; the mayor is Firhad Hakim , while the deputy mayor is Atin Ghosh. The city has an apolitical titular post, that of the Sheriff of Kolkata , which presides over various city-related functions and conferences. As the seat of the Government of West Bengal , Kolkata is home to not only the offices of the local governing agencies, but also the West Bengal Legislative Assembly ; the state secretariat, which is housed in the Writers' Building; and the Calcutta High Court . Most government establishments and institutions are housed in the centre of the city in B. B. D. Bagh (formerly known as Dalhousie Square). The Calcutta High Court is the oldest High Court in India. It was preceded by the Supreme Court of Judicature at Fort William which was established in 1774. The Calcutta High Court has jurisdiction over the state of West Bengal and the Union Territory of the Andaman and Nicobar Islands . Kolkata has lower courts: the Court of Small Causes and the City Civil Court decide civil matters; the Sessions Court rules in criminal cases. The Kolkata Police , headed by a police commissioner, is overseen by the West Bengal Ministry of Home Affairs . The Kolkata district elects two representatives to India's lower house, the Lok Sabha , and 11 representatives to the state legislative assembly. The Kolkata police district registered 15,510 Indian Penal Code cases in 2010, the 8th-highest total in the country. In 2010, the crime rate was 117.3 per 100,000, below the national rate of 187.6; it was the lowest rate among India's largest cities. The Kolkata Municipal Corporation supplies the city with potable water that is sourced from the Hooghly River; most of it is treated and purified at the Palta pumping station located in North 24 Parganas district. [ failed verification ] Roughly 95% of the 4,000 tonnes of refuse produced daily by the city is transported to the dumping grounds in Dhapa , which is east of the town. To promote the recycling of garbage and sewer water, agriculture is encouraged on the dumping grounds. Parts of the city lack proper sewerage, leading to unsanitary methods of waste disposal. In 1856, the Bengal Government appointed George Turnbull to be the Commissioner of Drainage and Sewerage to improve the city's sewerage. Turnbull's main job was to be the Chief Engineer of the East Indian Railway Company responsible for building the first railway 541 miles (871 km) from Howrah to Varanasi (then Benares ). Electricity is supplied by the privately operated Calcutta Electric Supply Corporation , or CESC, to the city proper; the West Bengal State Electricity Board supplies it in the suburbs. Fire services are handled by the West Bengal Fire Service , a state agency. As of 2012 [ update ] , the city had 16 fire stations. State-owned Bharat Sanchar Nigam Limited , or BSNL, as well as private enterprises, among them Vodafone Idea , Bharti Airtel , Reliance Jio are the leading telephone and cell phone service providers in the city. : 25–26 : 179 with Kolkata being the first city in India to have cell phone and 4G connectivity, the GSM and CDMA cellular coverage is extensive. As of 2010 [ update ] , Kolkata has 7 percent of the total broadband internet consumers in India; BSNL, VSNL, Tata Indicom, Sify, Hathway, Airtel, and Jio are among the main vendors. The Eastern Command of the Indian Army is based in the city. Being one of India's major city and the largest city in eastern and north-eastern India, Kolkata hosts diplomatic missions of many countries such as Australia, Bangladesh, Bhutan, Canada, People's Republic of China, France, Germany, Italy, Japan, Myanmar, Nepal, Russia, Sri Lanka, Switzerland, Thailand, United Kingdom and United States . The U.S Consulate in Kolkata is the US Department of State 's second-oldest Consulate and dates from 19 November 1792. The Diplomatic representation of more than 65 Countries and International Organization is present in Kolkata as Consulate office, honorary Consulate office, Cultural Centre, Deputy High Commission and Economic section and Trade Representation office. Public transport is provided by the Kolkata Suburban Railway , the Kolkata Metro , trams , rickshaws , taxis and buses. The suburban rail network connects the city's distant suburbs. Kolkata Metro is the oldest rapid transit system in India. According to a 2013 survey conducted by the International Association of Public Transport , in terms of a public transport system, Kolkata ranks among the top of the six Indian cities surveyed. The Kolkata Metro, in operation since 1984, is the oldest underground mass transit system in India. It spans the north–south length of the city. In 2020, part of the Second line was inaugurated to cover part of Salt Lake. This east–west line will connect Salt Lake with Howrah. The two lines cover a distance of 33.02 km (21 mi) . As of 2020 [ update ] , four Metro rail lines were under construction. Kolkata has five long-distance railway stations, located at Howrah (the largest railway complex in India), Sealdah , Kolkata , Shalimar and Santragachi , which connect Kolkata by rail to most cities in West Bengal and to other major cities in India. The city serves as the headquarters of three railway zones out of eighteen of the Indian Railways regional divisions—the Kolkata Metro Railways, Eastern Railway and the South-Eastern Railway . Kolkata has rail and road connectivity with Dhaka , the capital of Bangladesh. Buses, which are the most commonly used mode of transport, are run by government agencies and private operators. Kolkata is the only Indian city with a tram network, which was operated by the Calcutta Tramways Company . It has now renamed to West Bengal Transport Corporation . The slow-moving tram services are restricted to certain areas of the city. Water-logging, caused by heavy rains during the summer monsoon , sometimes interrupt transportation networks. The city has witnessed a steady increase in the number of registered vehicles; 2002 data showed an increase of 44% over a period of seven years. As of 2004 [ update ] , after adjusting for population density, the city's "road space" was only 6% compared to 23% in Delhi and 17% in Mumbai. The Kolkata Metro has somewhat eased traffic congestion, as has the addition of new roads and flyovers . Agencies operating long-distance bus services include the West Bengal Transport Corporation and various private operators. The city's main bus terminals are located at Esplanade and Babughat . The Kolkata–Delhi and Kolkata– Chennai prongs of the Golden Quadrilateral , and National Highway 12 start from the city. At present, Kolkata has two expressways , but they are not considered to be as separate dedicated expressways in the national level, as both are parts of the National Highway 16 (NH-16). They are Belghoria and Kona expressways. In the coming years, Kolkata will get dedicated expressways and will be connected directly with many major metropolises and cities of India, also internationally, to Nepal . They are as follows: Hired public conveyances include auto rickshaws , which often ply specific routes, and yellow metered taxis. Almost all of Kolkata's taxis are antiquated Hindustan Ambassadors by make; newer air-conditioned radio taxis are in service as well. In parts of the city, cycle rickshaws and hand-pulled rickshaws are patronised by the public for short trips. Netaji Subhas Chandra Bose International Airport , located in Dum Dum, about 16 km (9.9 mi) north-east of the city centre, operates domestic and international flights. In 2013, the airport was upgraded to handle increased air traffic. The Port of Kolkata , established in 1870, is India's oldest and the only major river port. The Kolkata Port Trust manages docks in Kolkata and Haldia . The port hosts passenger services to Port Blair , capital of the Andaman and Nicobar Islands; freighter service to ports throughout India and around the world is operated by the Shipping Corporation of India . Ferry services connect Kolkata with its twin city of Howrah , located across the Hooghly River. Kolkata Metro is the oldest rapid transit system in India. According to a 2013 survey conducted by the International Association of Public Transport , in terms of a public transport system, Kolkata ranks among the top of the six Indian cities surveyed. The Kolkata Metro, in operation since 1984, is the oldest underground mass transit system in India. It spans the north–south length of the city. In 2020, part of the Second line was inaugurated to cover part of Salt Lake. This east–west line will connect Salt Lake with Howrah. The two lines cover a distance of 33.02 km (21 mi) . As of 2020 [ update ] , four Metro rail lines were under construction. Kolkata has five long-distance railway stations, located at Howrah (the largest railway complex in India), Sealdah , Kolkata , Shalimar and Santragachi , which connect Kolkata by rail to most cities in West Bengal and to other major cities in India. The city serves as the headquarters of three railway zones out of eighteen of the Indian Railways regional divisions—the Kolkata Metro Railways, Eastern Railway and the South-Eastern Railway . Kolkata has rail and road connectivity with Dhaka , the capital of Bangladesh. Buses, which are the most commonly used mode of transport, are run by government agencies and private operators. Kolkata is the only Indian city with a tram network, which was operated by the Calcutta Tramways Company . It has now renamed to West Bengal Transport Corporation . The slow-moving tram services are restricted to certain areas of the city. Water-logging, caused by heavy rains during the summer monsoon , sometimes interrupt transportation networks. The city has witnessed a steady increase in the number of registered vehicles; 2002 data showed an increase of 44% over a period of seven years. As of 2004 [ update ] , after adjusting for population density, the city's "road space" was only 6% compared to 23% in Delhi and 17% in Mumbai. The Kolkata Metro has somewhat eased traffic congestion, as has the addition of new roads and flyovers . Agencies operating long-distance bus services include the West Bengal Transport Corporation and various private operators. The city's main bus terminals are located at Esplanade and Babughat . The Kolkata–Delhi and Kolkata– Chennai prongs of the Golden Quadrilateral , and National Highway 12 start from the city. At present, Kolkata has two expressways , but they are not considered to be as separate dedicated expressways in the national level, as both are parts of the National Highway 16 (NH-16). They are Belghoria and Kona expressways. In the coming years, Kolkata will get dedicated expressways and will be connected directly with many major metropolises and cities of India, also internationally, to Nepal . They are as follows: Hired public conveyances include auto rickshaws , which often ply specific routes, and yellow metered taxis. Almost all of Kolkata's taxis are antiquated Hindustan Ambassadors by make; newer air-conditioned radio taxis are in service as well. In parts of the city, cycle rickshaws and hand-pulled rickshaws are patronised by the public for short trips. Netaji Subhas Chandra Bose International Airport , located in Dum Dum, about 16 km (9.9 mi) north-east of the city centre, operates domestic and international flights. In 2013, the airport was upgraded to handle increased air traffic. The Port of Kolkata , established in 1870, is India's oldest and the only major river port. The Kolkata Port Trust manages docks in Kolkata and Haldia . The port hosts passenger services to Port Blair , capital of the Andaman and Nicobar Islands; freighter service to ports throughout India and around the world is operated by the Shipping Corporation of India . Ferry services connect Kolkata with its twin city of Howrah , located across the Hooghly River. As of 2011 [ update ] , the healthcare system in Kolkata consists of 48 government hospitals, mostly under the Department of Health & Family Welfare , Government of West Bengal, and 366 private medical establishments; these establishments provide the city with 27,687 hospital beds. For every 10,000 people in the city, there are 61.7 hospital beds, which is higher than the national average of 9 hospital beds per 10,000. Ten medical and dental colleges are located in the Kolkata metropolitan area which act as tertiary referral hospitals in the state. The Calcutta Medical College , founded in 1835, was the first institution in Asia to teach modern medicine. However, These facilities are inadequate to meet the healthcare needs of the city. More than 78% in Kolkata prefer the private medical sector over the public medical sector, : 109 due to the overburdening of the public health sector, the lack of a nearby facility, and excessive waiting times at government facilities. : 61 According to the Indian 2005 National Family Health Survey, only a small proportion of Kolkata households were covered under any health scheme or health insurance . : 41 The total fertility rate in Kolkata was 1.4, the lowest among the eight cities surveyed. : 45 In Kolkata, 77% of the married women used contraceptives , which was the highest among the cities surveyed, but use of modern contraceptive methods was the lowest (46%). : 47 The infant mortality rate in Kolkata was 41 per 1,000 live births, and the mortality rate for children under five was 49 per 1,000 live births. : 48 Among the surveyed cities, Kolkata stood second (5%) for children who had not had any vaccinations under the Universal Immunization Programme as of 2005 [ update ] . : 48 Kolkata ranked second with access to an anganwadi centre under the Integrated Child Development Services (ICDS) programme for 57% of the children between 0 and 71 months. : 51 The proportion of malnourished , anaemic and underweight children in Kolkata was less in comparison to other surveyed cities. : 54–55 About 18% of the men and 30% of the women in Kolkata are obese —the majority of them belonging to the non-poor strata of society. : 105 In 2005, Kolkata had the highest percentage (55%) among the surveyed cities of anaemic women, while 20% of the men in Kolkata were anaemic. : 56–57 Diseases like diabetes , asthma , goitre and other thyroid disorders were found in large numbers of people. : 57–59 Tropical diseases like malaria , dengue and chikungunya are prevalent in Kolkata, though their incidence is decreasing. Kolkata is one of the districts in India with a high number of people with AIDS ; it has been designated a district prone to high risk. As of 2014, because of higher air pollution , the life expectancy of a person born in the city is four years fewer than in the suburbs. Kolkata's schools are run by the state government or private organisations, many of which are religious. Bengali and English are the primary languages of instruction; Urdu and Hindi are also used, particularly in central Kolkata. Schools in Kolkata follow the "10+2+3" plan . After completing their secondary education, students typically enroll in schools that have a higher secondary facility and are affiliated with the West Bengal Council of Higher Secondary Education , the ICSE , or the CBSE . They usually choose a focus on liberal arts, business, or science. Vocational programs are also available. Some Kolkata schools, for example South Point School , La Martiniere Calcutta , Calcutta Boys' School , St. James' School (Kolkata) , St. Xavier's Collegiate School and Loreto House , have been ranked amongst the best schools in the country. As of 2010 [ update ] , the Kolkata urban agglomeration is home to 14 universities run by the state government. The colleges are each affiliated with a university or institution based either in Kolkata or elsewhere in India. Aliah University which was founded in 1780 as Mohammedan College of Calcutta is the oldest post-secondary educational institution of the city. The University of Calcutta , founded in 1857, is the first modern university in South Asia. Presidency College, Kolkata (formerly Hindu College between 1817 and 1855), founded in 1855, was one of the oldest colleges in India. It was affiliated with the University of Calcutta until 2010 when it was converted to Presidency University, Kolkata in 2010. Bengal Engineering and Science University (BESU) is the second oldest engineering institution of the country located in Howrah. An Institute of National Importance , BESU was converted to India's first IIEST . Jadavpur University is known for its arts, science, and engineering faculties. The Indian Institute of Management Calcutta , which was the first of the Indian Institutes of Management , was established in 1961 at Joka , a locality in the south-western suburbs. Kolkata also houses the Indian Institute of Foreign Trade , which was started here in the year 2006. The West Bengal National University of Juridical Sciences is one of India's autonomous law schools , and the Indian Statistical Institute is a public research institute and university. State owned Maulana Abul Kalam Azad University of Technology , West Bengal (MAKAUT, WB), formerly West Bengal University of Technology (WBUT) is the largest Technological University in terms of student enrollment and number of Institutions affiliated by it. Private institutions include the Ramakrishna Mission Vivekananda Educational and Research Institute and University of Engineering & Management (UEM) . Notable scholars who were born, worked or studied in Kolkata include physicists Satyendra Nath Bose , Meghnad Saha , and Jagadish Chandra Bose ; chemist Prafulla Chandra Roy ; statisticians Prasanta Chandra Mahalanobis and Anil Kumar Gain ; physician Upendranath Brahmachari ; educator Ashutosh Mukherjee ; and Nobel laureates Rabindranath Tagore , C. V. Raman , and Amartya Sen . Kolkata houses many research institutes like Indian Association for the Cultivation of Science (IACS), Indian Institute of Chemical Biology (IICB), Indian Institute of Science Education and Research (IISER), Bose Institute , Saha Institute of Nuclear Physics (SINP), Centre for Studies in Social Sciences, Calcutta , All India Institute of Hygiene and Public Health , Central Glass and Ceramic Research Institute (CGCRI), S.N. Bose National Centre for Basic Sciences (SNBNCBS), Indian Institute of Social Welfare and Business Management (IISWBM), National Institute of Pharmaceutical Education and Research, Kolkata , Variable Energy Cyclotron Centre (VECC) and Indian Centre for Space Physics . Nobel laureate Sir C. V. Raman did his groundbreaking work in Raman effect in IACS.Kolkata is known for its literary, artistic and revolutionary heritage; as the former capital of India, it was the birthplace of modern Indian literary and artistic thought. Kolkata has been called the "City of Furious, Creative Energy" as well as the "cultural [or literary] capital of India". The presence of paras , which are neighbourhoods that possess a strong sense of community, is characteristic of the city. Typically, each para has its own community club and on occasion, a playing field. Residents engage in addas , or leisurely chats, that often take the form of freestyle intellectual conversation. The city has a tradition of political graffiti depicting everything from outrageous slander to witty banter and limericks, caricatures and propaganda. Kolkata has many buildings adorned with Indo-Islamic and Indo-Saracenic architectural motifs. Several well-maintained major buildings from the colonial period have been declared "heritage structures"; others are in various stages of decay. Established in 1814 as the nation's oldest museum, the Indian Museum houses large collections that showcase Indian natural history and Indian art . Marble Palace is a classic example of a European mansion that was built in the city. The Victoria Memorial , a place of interest in Kolkata , has a museum documenting the city's history. The National Library of India is the leading public library in the country while Science City is the largest science centre in the Indian subcontinent . The popularity of commercial theatres in the city has declined since the 1980s. : 99 Group theatres of Kolkata , a cultural movement that started in the 1940s contrasting with the then-popular commercial theatres, are theatres that are not professional or commercial, and are centres of various experiments in theme, content, and production; group theatres use the proscenium stage to highlight socially relevant messages. : 99 Chitpur locality of the city houses multiple production companies of jatra , a tradition of folk drama popular in rural Bengal. Kolkata is the home of the Bengali cinema industry, dubbed "Tollywood" for Tollygunj , where most of the state's film studios are located. Its long tradition of art films includes globally acclaimed film directors such as Academy Award -winning director Satyajit Ray , Ritwik Ghatak , Mrinal Sen , Tapan Sinha and contemporary directors such as Aparna Sen , Buddhadeb Dasgupta , Goutam Ghose and Rituparno Ghosh . During the 19th and 20th centuries, Bengali literature was modernised through the works of authors such as Ishwar Chandra Vidyasagar , Bankim Chandra Chattopadhyay , Michael Madhusudan Dutt , Rabindranath Tagore , Kazi Nazrul Islam and Sarat Chandra Chattopadhyay . Coupled with social reforms led by Ram Mohan Roy , Swami Vivekananda and others, this constituted a major part of the Bengal Renaissance . The middle and latter parts of the 20th century witnessed the arrival of post-modernism, as well as literary movements such as those espoused by the Kallol movement, hungryalists and the little magazines . Large majority of publishers of the city is concentrated in and around College Street , "... a half-mile of bookshops and bookstalls spilling over onto the pavement", selling new and used books. Kalighat painting originated in 19th century Kolkata as a local style that reflected a variety of themes including mythology and quotidian life. The Government College of Art and Craft , founded in 1864, has been the cradle as well as workplace of eminent artists including Abanindranath Tagore , Jamini Roy and Nandalal Bose . The art college was the birthplace of the Bengal school of art that arose as an avant garde and nationalist movement reacting against the prevalent academic art styles in the early 20th century. The Academy of Fine Arts and other art galleries hold regular art exhibitions. The city is recognised for its appreciation of Rabindra sangeet (songs written by Rabindranath Tagore) and Indian classical music , with important concerts and recitals, such as Dover Lane Music Conference , being held throughout the year; Bengali popular music, including baul folk ballads , kirtans and Gajan festival music; and modern music, including Bengali-language adhunik songs. Since the early 1990s, new genres have emerged, including one comprising alternative folk–rock Bengali bands . Another new style, jibonmukhi gaan ("songs about life"), is based on realism . : 105 Key elements of Kolkata's cuisine include rice and a fish curry known as machher jhol , which can be accompanied by desserts such as roshogolla , sandesh , and a sweet yoghurt known as mishti dohi . Bengal's large repertoire of seafood dishes includes various preparations of ilish , a fish that is a favourite among Calcuttans. Street foods such as beguni (fried battered eggplant slices), kati roll (flatbread roll with vegetable or chicken, mutton or egg stuffing), phuchka (a deep-fried crêpe with tamarind sauce) and Indian Chinese cuisine from Chinatown are popular. Though Bengali women traditionally wear the sari , the shalwar kameez and Western attire is gaining acceptance among younger women. Western-style dress has greater acceptance among men, although the traditional dhoti and kurta are seen during festivals. Durga Puja , held in September–October, is Kolkata's most important and largest festival; it is an occasion for glamorous celebrations and artistic decorations. The Bengali New Year, known as Poila Boishak , as well as the harvest festival of Poush Parbon are among the city's other festivals; also celebrated are Kali Puja , Diwali , Chhaith , Jitiya , Holi , Jagaddhatri Puja, Saraswati Puja , Rathayatra , Janmashtami , Maha Shivratri , Vishwakarma Puja , Lakshmi Puja , Ganesh Chathurthi , Makar Sankranti , Gajan , Kalpataru Day , Bhai Phonta , Maghotsab, Eid , Muharram , Christmas , Buddha Purnima and Mahavir Jayanti . Cultural events include the Rabindra Jayanti , Independence Day (15 August), Republic Day (26 January), Kolkata Book Fair , the Dover Lane Music Festival, the Kolkata Film Festival , Nandikar's National Theatre Festival , Statesman Vintage & Classic Car Rally and Gandhi Jayanti .The first newspaper in India, the Bengal Gazette started publishing from the city in 1780. Among Kolkata's widely circulated Bengali-language newspapers are Anandabazar Patrika , Bartaman , Ei Samay Sangbadpatra , Sangbad Pratidin , Aajkaal , Dainik Statesman and Ganashakti . The Statesman and The Telegraph are two major English-language newspapers that are produced and published from Kolkata. Other popular English-language newspapers published and sold in Kolkata include The Times of India , Hindustan Times , The Hindu , The Indian Express and the Asian Age . As the largest trading centre in East India, Kolkata has several high-circulation financial dailies, including The Economic Times , The Financial Express , Business Line and Business Standard . Vernacular newspapers, such as those in the Hindi , Urdu , Gujarati , Odia , Punjabi and Chinese languages, are read by minorities. Major periodicals based in Kolkata include Desh , Sananda , Saptahik Bartaman , Unish-Kuri , Anandalok and Anandamela . Historically, Kolkata has been the centre of the Bengali little magazine movement . All India Radio , the national state-owned radio broadcaster, airs several AM radio stations in the city. Kolkata has 10 local radio stations broadcasting on FM , including three from AIR. India's state-owned television broadcaster, Doordarshan , provides two free-to-air terrestrial channels, while a mix of Bengali, Hindi, English, and other regional channels are accessible via cable subscription , direct-broadcast satellite services, or internet-based television . Bengali-language 24-hour television news channels include ABP Ananda , News18 Bangla , Kolkata TV , Zee 24 Ghanta , TV9 Bangla and Republic Bangla . The most popular sports in Kolkata are football and cricket . Unlike most parts of India, the residents show significant passion for football. Indian Football Association , the oldest football association of the country is based here. It administers football in West Bengal. Kolkata is home to India's top football clubs such as Mohun Bagan A.C. , East Bengal Club and the Mohammedan Sporting Club . The Calcutta Football League , which is the oldest football league in Asia was started in 1898. Mohun Bagan A.C., one of the oldest football clubs in Asia, is the only organisation to be dubbed as "National Club of India". Two clubs of the city - Mohun Bagan Super Giant and East Bengal FC compete in the Indian Super League (ISL). Football matches between Mohun Bagan and East Bengal, called as the Kolkata Derby , witness large audience attendance and rivalry between patrons. The multi-use Salt Lake Stadium , also known as Vivekananda Yuba Bharati Krirangan, is India's second largest stadium by seating capacity . Most matches of the 2017 FIFA U-17 World Cup were played in this stadium including both Semi-final matches and the Final match. Kolkata also accounted for 45% of total attendance in 2017 FIFA U-17 World Cup with an average of 55,345 spectators. The Calcutta Cricket and Football Club is the second-oldest cricket club in the world. As in the rest of India, cricket is popular in Kolkata and is played on various grounds throughout the city. Kolkata is home to Indian Premier League (IPL) franchise Kolkata Knight Riders and also the Cricket Association of Bengal which regulates cricket in West Bengal and the Bengal cricket team . Tournaments, especially those involving cricket, football, badminton and carrom , are regularly organised here on an inter-locality or inter-club basis. The Maidan, a vast field that serves as the city's largest park, hosts several minor football and cricket clubs and coaching institutes. Eden Gardens , which has a capacity of 80,000 as of 2017 [ update ] , hosted the final match of the 1987 Cricket World Cup . Kolkata's Netaji Indoor Stadium served as host of the 1981 Asian Basketball Championship , where India's national basketball team finished 5th, ahead of teams that belong to Asia's basketball elite, such as Iran . The city has three 18-hole golf courses. The oldest is at the Royal Calcutta Golf Club , the first golf club built outside the United Kingdom. The other two are located at the Tollygunge Club and at Fort William . The Royal Calcutta Turf Club hosts horse racing and polo matches. The Calcutta Polo Club is considered the oldest extant polo club in the world. The Calcutta Racket Club is a squash and racquet club in Kolkata. It was founded in 1793, making it one of the oldest rackets clubs in the world, and the first in the Indian subcontinent. The Calcutta South Club is a venue for national and international tennis tournaments; it held the first grass-court national championship in 1946. In the period 2005–2007, Sunfeast Open , a tier-III tournament on the Women's Tennis Association circuit, was held in the Netaji Indoor Stadium; it has since been discontinued. The Calcutta Rowing Club hosts rowing heats and training events. Kolkata, considered the leading centre of rugby union in India , gives its name to the oldest international tournament in rugby union, the Calcutta Cup . The Automobile Association of Eastern India, established in 1904, and the Bengal Motor Sports Club are involved in promoting motor sports and car rallies in Kolkata and West Bengal. The Beighton Cup , an event organised by the Bengal Hockey Association and first played in 1895, is India's oldest field hockey tournament; it is usually held on the Mohun Bagan Ground of the Maidan. Athletes from Kolkata include Sourav Ganguly , Pankaj Roy and Jhulan Goswami , who are former captains of the Indian national cricket team ; Olympic tennis bronze medalist Leander Paes , golfer Arjun Atwal , and former footballers Sailen Manna , Chuni Goswami , P. K. Banerjee and Subrata Bhattacharya .

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Smallpox

Smallpox was an infectious disease caused by variola virus (often called smallpox virus), which belongs to the genus Orthopoxvirus . The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) certified the global eradication of the disease in 1980, making smallpox the only human disease to have been eradicated to date. The initial symptoms of the disease included fever and vomiting. This was followed by formation of ulcers in the mouth and a skin rash . Over a number of days, the skin rash turned into the characteristic fluid-filled blisters with a dent in the center. The bumps then scabbed over and fell off, leaving scars. The disease was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person or (rarely) via contaminated objects . Prevention was achieved mainly through the smallpox vaccine . Once the disease had developed, certain antiviral medications could potentially have helped, but such medications did not become available until after the disease was eradicated. The risk of death was about 30%, with higher rates among babies. Often, those who survived had extensive scarring of their skin, and some were left blind. The earliest evidence of the disease dates to around 1500 BC in Egyptian mummies . The disease historically occurred in outbreaks . In 18th-century Europe, it is estimated that 400,000 people died from the disease per year, and that one-third of all cases of blindness were due to smallpox. Smallpox is estimated to have killed up to 300 million people in the 20th century and around 500 million people in the last 100 years of its existence. Earlier deaths included six European monarchs , including Louis XV of France in 1774. As recently as 1967, 15 million cases occurred a year. Inoculation for smallpox appears to have started in China around the 1500s. Europe adopted this practice from Asia in the first half of the 18th century. In 1796, Edward Jenner introduced the modern smallpox vaccine. In 1967, the WHO intensified efforts to eliminate the disease. Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest (a disease of even-toed ungulates ) in 2011. The term "smallpox" was first used in England in the 16th century to distinguish the disease from syphilis , which was then known as the "great pox". Other historical names for the disease include pox, speckled monster, and red plague. There are two forms of the smallpox. Variola major is the severe and most common form, with a more extensive rash and higher fever. Variola minor is a less common presentation, causing less severe disease, typically discrete smallpox, with historical death rates of 1% or less. Subclinical ( asymptomatic ) infections with variola virus were noted but were not common. In addition, a form called variola sine eruptione (smallpox without rash) was seen generally in vaccinated persons. This form was marked by a fever that occurred after the usual incubation period and could be confirmed only by antibody studies or, rarely, by viral culture . In addition, there were two very rare and fulminating types of smallpox, the malignant (flat) and hemorrhagic forms, which were usually fatal.The initial symptoms were similar to other viral diseases that are still extant, such as influenza and the common cold : fever of at least 38.3 °C (101 °F) , muscle pain , malaise , headache and fatigue. As the digestive tract was commonly involved, nausea, vomiting, and backache often occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15, the first visible lesions – small reddish spots called enanthem – appeared on mucous membranes of the mouth, tongue, palate , and throat, and the temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva. Variola virus tended to attack skin cells, causing the characteristic pimples, or macules , associated with the disease. A rash developed on the skin 24 to 48 hours after lesions on the mucous membranes appeared. Typically the macules first appeared on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process took no more than 24 to 36 hours, after which no new lesions appeared. At this point, variola major disease could take several very different courses, which resulted in four types of smallpox disease based on the Rao classification: ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and the malignant and hemorrhagic forms were usually fatal. The modified form was almost never fatal. In early hemorrhagic cases, hemorrhages occurred before any skin lesions developed. The incubation period between contraction and the first obvious symptoms of the disease was 7–14 days. At least 90% of smallpox cases among unvaccinated persons were of the ordinary type. In this form of the disease, by the second day of the rash the macules had become raised papules . By the third or fourth day, the papules had filled with an opalescent fluid to become vesicles . This fluid became opaque and turbid within 24–48 hours, resulting in pustules . By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to the touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars. Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%. Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form, the prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox. Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox . In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10% of cases, and most (72%) were children. Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of viremia . The prodromal symptoms continued even after the onset of the rash. The rash on the mucous membranes ( enanthem ) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign. This form is thought to be caused by deficient cell-mediated immunity to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs. Hemorrhagic smallpox is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera . This form develops in approximately 2% of infections and occurs mostly in adults. Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black, hence this form of the disease is also referred to as variola nigra or "black pox". Hemorrhagic smallpox has very rarely been caused by variola minor virus. While bleeding may occur in mild cases and not affect outcomes, hemorrhagic smallpox is typically fatal. Vaccination does not appear to provide any immunity to either form of hemorrhagic smallpox and some cases even occurred among people that were revaccinated shortly before. It has two forms. The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa ) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain. The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes , skeletal muscles, pericardium , liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%. There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica ). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa ), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin . This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. At least 90% of smallpox cases among unvaccinated persons were of the ordinary type. In this form of the disease, by the second day of the rash the macules had become raised papules . By the third or fourth day, the papules had filled with an opalescent fluid to become vesicles . This fluid became opaque and turbid within 24–48 hours, resulting in pustules . By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to the touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars. Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%. Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%. Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form, the prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox. Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with chickenpox . In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10% of cases, and most (72%) were children. Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of viremia . The prodromal symptoms continued even after the onset of the rash. The rash on the mucous membranes ( enanthem ) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign. This form is thought to be caused by deficient cell-mediated immunity to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs. Hemorrhagic smallpox is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera . This form develops in approximately 2% of infections and occurs mostly in adults. Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black, hence this form of the disease is also referred to as variola nigra or "black pox". Hemorrhagic smallpox has very rarely been caused by variola minor virus. While bleeding may occur in mild cases and not affect outcomes, hemorrhagic smallpox is typically fatal. Vaccination does not appear to provide any immunity to either form of hemorrhagic smallpox and some cases even occurred among people that were revaccinated shortly before. It has two forms. The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa ) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain. The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes , skeletal muscles, pericardium , liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%. There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica ). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa ), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin . This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. The early or fulminant form of hemorrhagic smallpox (referred to as purpura variolosa ) begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain. The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, conjunctiva and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before. Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes , skeletal muscles, pericardium , liver, gonads and bladder. Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy. This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males). The case fatality rate of early hemorrhagic smallpox approaches 100%. There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or variolosa pustula hemorrhagica ). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease. Bleeding appears in the early eruptive period (but later than that seen in purpura variolosa ), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form. Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin . This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain. Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence. The case fatality rate for late hemorrhagic smallpox is around 90–95%. Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox. Smallpox is caused by infection with variola virus, which belongs to the family Poxviridae , subfamily Chordopoxvirinae , genus Orthopoxvirus . The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago. The wide range of dates is due to the different records used to calibrate the molecular clock . One clade was the variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both alastrim (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago. A second estimate has placed the separation of variola virus from Taterapox (an Orthopoxvirus of some African rodents including gerbils ) at 3,000 to 4,000 years ago. This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses , the divergence date of variola virus from Taterapox has been estimated to be 50,000 years ago. While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed. Examination of a strain that dates from c. 1650 found that this strain was basal to the other presently sequenced strains. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries. Variola virus is large and brick-shaped and is approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. Four orthopoxviruses cause infection in humans: variola, vaccinia , cowpox , and monkeypox . Variola virus infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus . To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses , the most important of which is a viral-associated DNA-dependent RNA polymerase . Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin . Infection with either variola major virus or variola minor virus confers immunity against the other. The more common, infectious form of the disease was caused by the variola major virus strain. Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpox's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola. The genome of variola major virus is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes . The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of the central region of the genome is highly consistent across orthopoxviruses , and the arrangement of genes is consistent across chordopoxviruses The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins , DNA replication , transcription , and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses . These regions contain proteins that modulate the hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop , a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames , and short tandemly repeating sequences of varying number and length. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with the genome of vaccinia , a related virus used for vaccination against smallpox. Gene expression of variola virus occurs entirely within the cytoplasm of the host cell , and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to the replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of a host cell varies across the poxviridae . Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles. These proteins are then packaged into new infectious virions capable of infecting other cells. Two live samples of variola major virus remain, one in the United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia. Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the WHO and the World Health Assembly (WHA). Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism. Vaccinia virus, which is used to vaccinate for smallpox, is also under research as a viral vector for vaccines for unrelated diseases. The genome of variola major virus was first sequenced in its entirety in the 1990s. The complete coding sequence is publicly available online. The current reference sequence for variola major virus was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during the WHO eradication campaign. A genome browser for a complete database of annotated sequences of variola virus and other poxviruses is publicly available through the Viral Bioinformatics Resource Center . The WHO currently bans genetic engineering of the variola virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add a marker gene . This gene, called GFP , or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA . When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus . The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia , a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of variola major and causing other scientists to question their motives. Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort. Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus. Smallpox was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections was highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year. Age distribution of smallpox infections depended on acquired immunity . Vaccination immunity declined over time and was probably lost within thirty years. Smallpox was not known to be transmitted by insects or animals and there was no asymptomatic carrier state. Transmission occurred through inhalation of airborne variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person. Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects ( fomites ), but this was found to be rare. Also rarely, smallpox was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta , but the incidence of congenital smallpox was relatively low. Smallpox was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact. Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last smallpox scab fell off. The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago. The wide range of dates is due to the different records used to calibrate the molecular clock . One clade was the variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both alastrim (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago. A second estimate has placed the separation of variola virus from Taterapox (an Orthopoxvirus of some African rodents including gerbils ) at 3,000 to 4,000 years ago. This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses , the divergence date of variola virus from Taterapox has been estimated to be 50,000 years ago. While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed. Examination of a strain that dates from c. 1650 found that this strain was basal to the other presently sequenced strains. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries.Variola virus is large and brick-shaped and is approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. Four orthopoxviruses cause infection in humans: variola, vaccinia , cowpox , and monkeypox . Variola virus infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus . To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses , the most important of which is a viral-associated DNA-dependent RNA polymerase . Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin . Infection with either variola major virus or variola minor virus confers immunity against the other. The more common, infectious form of the disease was caused by the variola major virus strain. Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpox's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola. The genome of variola major virus is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes . The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of the central region of the genome is highly consistent across orthopoxviruses , and the arrangement of genes is consistent across chordopoxviruses The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins , DNA replication , transcription , and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses . These regions contain proteins that modulate the hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop , a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames , and short tandemly repeating sequences of varying number and length. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with the genome of vaccinia , a related virus used for vaccination against smallpox. Gene expression of variola virus occurs entirely within the cytoplasm of the host cell , and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to the replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of a host cell varies across the poxviridae . Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles. These proteins are then packaged into new infectious virions capable of infecting other cells. The more common, infectious form of the disease was caused by the variola major virus strain.Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpox's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus. Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980. Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola.The genome of variola major virus is about 186,000 base pairs in length. It is made from linear double stranded DNA and contains the coding sequence for about 200 genes . The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome. The coding sequence of the central region of the genome is highly consistent across orthopoxviruses , and the arrangement of genes is consistent across chordopoxviruses The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural proteins , DNA replication , transcription , and mRNA synthesis. The ends of the genome vary more across strains and species of orthopoxviruses . These regions contain proteins that modulate the hosts' immune systems, and are primarily responsible for the variability in virulence across the orthopoxvirus family. These terminal regions in poxviruses are inverted terminal repetitions (ITR) sequences. These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA Components of the ITR sequences include an incompletely base paired A/T rich hairpin loop , a region of roughly 100 base pairs necessary for resolving concatomeric DNA (a stretch of DNA containing multiple copies of the same sequence), a few open reading frames , and short tandemly repeating sequences of varying number and length. The ITRs of poxviridae vary in length across strains and species. The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with the genome of vaccinia , a related virus used for vaccination against smallpox. Gene expression of variola virus occurs entirely within the cytoplasm of the host cell , and follows a distinct progression during infection. After entry of an infectious virion into a host cell, synthesis of viral mRNA can be detected within 20 minutes. About half of the viral genome is transcribed prior to the replication of viral DNA. The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion. These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes. Unlike most DNA viruses, DNA replication in variola virus and other poxviruses takes place within the cytoplasm of the infected cell. The exact timing of DNA replication after infection of a host cell varies across the poxviridae . Recombination of the genome occurs within actively infected cells. Following the onset of viral DNA replication, an intermediate set of genes codes for transcription factors of late gene expression. The products of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral RNA polymerase and other essential enzymes for new viral particles. These proteins are then packaged into new infectious virions capable of infecting other cells. Two live samples of variola major virus remain, one in the United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia. Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the WHO and the World Health Assembly (WHA). Most research on poxviruses is performed using the closely related Vaccinia virus as a model organism. Vaccinia virus, which is used to vaccinate for smallpox, is also under research as a viral vector for vaccines for unrelated diseases. The genome of variola major virus was first sequenced in its entirety in the 1990s. The complete coding sequence is publicly available online. The current reference sequence for variola major virus was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during the WHO eradication campaign. A genome browser for a complete database of annotated sequences of variola virus and other poxviruses is publicly available through the Viral Bioinformatics Resource Center . The WHO currently bans genetic engineering of the variola virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add a marker gene . This gene, called GFP , or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA . When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus . The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia , a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of variola major and causing other scientists to question their motives. Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort. Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus. The WHO currently bans genetic engineering of the variola virus. However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add a marker gene . This gene, called GFP , or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light. The insertion of this gene, which would not influence the virulence of the virus, would be the only allowed modification of the genome. The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples. The recommendation could only take effect if approved by the WHA . When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time. Addition of the GFP gene to the Vaccinia genome is routinely performed during research on the closely related Vaccinia virus . The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus. Vaccinia , a cousin of the variola virus, was artificially synthesized in 2002 by NIH scientists. They used a previously established method that involved using a recombinant viral genome to create a self-replicating bacterial plasmid that produced viral particles. In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox. The researchers argued that their work would be beneficial to creating a safer and more effective vaccine for smallpox, although an effective vaccine is already available. The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of variola major and causing other scientists to question their motives. Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort. Although the WHO bans individual laboratories from synthesizing more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with malicious intentions could compile, from multiple sources, the full synthetic genome necessary to produce viable virus. Smallpox was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections was highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year. Age distribution of smallpox infections depended on acquired immunity . Vaccination immunity declined over time and was probably lost within thirty years. Smallpox was not known to be transmitted by insects or animals and there was no asymptomatic carrier state. Transmission occurred through inhalation of airborne variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person. Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects ( fomites ), but this was found to be rare. Also rarely, smallpox was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta , but the incidence of congenital smallpox was relatively low. Smallpox was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact. Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last smallpox scab fell off. Once inhaled, the variola virus invaded the mucus membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional lymph nodes and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, widespread lysis of infected cells occurred and the virus could be found in the bloodstream in large numbers, a condition known as viremia . This resulted in the second wave of multiplication in the spleen , bone marrow , and lymph nodes.The clinical definition of ordinary smallpox is an illness with acute onset of fever equal to or greater than 38.3 °C (101 °F) followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause. When a clinical case was observed, smallpox was confirmed using laboratory tests. Microscopically , poxviruses produce characteristic cytoplasmic inclusion bodies , the most important of which are known as Guarnieri bodies , and are the sites of viral replication . Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but the absence of Guarnieri bodies could not be used to rule out smallpox. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. All orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. If particles with the characteristic morphology of herpesviruses are seen this will eliminate smallpox and other orthopoxvirus infections. Definitive laboratory identification of variola virus involved growing the virus on chorioallantoic membrane (part of a chicken embryo ) and examining the resulting pock lesions under defined temperature conditions. Strains were characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measured variola virus-specific immunoglobulin and antigen were also developed to assist in the diagnosis of infection. Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox could be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly the same size since the viral effect progresses more uniformly. A variety of laboratory methods were available for detecting chickenpox in the evaluation of suspected smallpox cases. The earliest procedure used to prevent smallpox was inoculation with variola minor virus (a method later known as variolation after the introduction of smallpox vaccine to avoid possible confusion), which likely occurred in India, Africa, and China well before the practice arrived in Europe. The idea that inoculation originated in India has been challenged, as few of the ancient Sanskrit medical texts described the process of inoculation. Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming dynasty . If successful, inoculation produced lasting immunity to smallpox. Because the person was infected with variola virus, a severe infection could result, and the person could transmit smallpox to others. Variolation had a 0.5–2 percent mortality rate, considerably less than the 20–30 percent mortality rate of the disease. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . Lady Mary Wortley Montagu observed smallpox inoculation during her stay in the Ottoman Empire , writing detailed accounts of the practice in her letters, and enthusiastically promoted the procedure in England upon her return in 1718. According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia . Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". In 1721, Cotton Mather and colleagues provoked controversy in Boston by inoculating hundreds. After publishing The present method of inoculating for the small-pox in 1767, Dr Thomas Dimsdale was invited to Russia to variolate the Empress Catherine the Great of Russia and her son, Grand Duke Paul , which he successfully did in 1768. In 1796, Edward Jenner , a doctor in Berkeley, Gloucestershire , rural England, discovered that immunity to smallpox could be produced by inoculating a person with material from a cowpox lesion. Cowpox is a poxvirus in the same family as variola. Jenner called the material used for inoculation vaccine from the root word vacca , which is Latin for cow. The procedure was much safer than variolation and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by the vaccinia virus. Vaccinia is in the same family as cowpox and variola virus but is genetically distinct from both. The origin of the vaccinia virus and how it came to be in the vaccine are not known. The current formulation of the smallpox vaccine is a live virus preparation of the infectious vaccinia virus. The vaccine is given using a bifurcated (two-pronged) needle that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) several times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a "Jennerian vesicle") which fills with pus and begins to drain. During the second week, the blister begins to dry up, and a scab forms. The scab falls off in the third week, leaving a small scar. The antibodies induced by the vaccinia vaccine are cross-protective for other orthopoxviruses, such as monkeypox, cowpox, and variola (smallpox) viruses. Neutralizing antibodies are detectable 10 days after first-time vaccination and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95 percent of those vaccinated. Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, the immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3 percent; it was 7 percent among those vaccinated 11 to 20 years prior, and 11 percent among those vaccinated 20 or more years before infection. By contrast, 52 percent of unvaccinated persons died. There are side effects and risks associated with the smallpox vaccine. In the past, about 1 out of 1,000 people vaccinated for the first time experienced serious, but non-life-threatening, reactions, including toxic or allergic reaction at the site of the vaccination ( erythema multiforme ), spread of the vaccinia virus to other parts of the body, and spread to other individuals. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1 million (0.000198 percent) who receive the vaccine may die as a result, most often the result of postvaccinial encephalitis or severe necrosis in the area of vaccination (called progressive vaccinia ). Given these risks, as smallpox became effectively eradicated and the number of naturally occurring cases fell below the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United States in 1972 and was abandoned in most European countries in the early 1970s. Routine vaccination of health care workers was discontinued in the U.S. in 1976, and among military recruits in 1990 (although military personnel deploying to the Middle East and Korea still receive the vaccination ). By 1986, routine vaccination had ceased in all countries. It is now primarily recommended for laboratory workers at risk for occupational exposure. However, the possibility of variola virus being used as a biological weapon has rekindled interest in the development of newer vaccines. The smallpox vaccine is also effective in, and therefore administered for, the prevention of monkeypox . Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination four to seven days after exposure can offer some protection from disease or may modify the severity of the disease. Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock , such as fluid resuscitation . People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns . In July 2018, the Food and Drug Administration approved tecovirimat , the first drug approved for treatment of smallpox. Antiviral treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir might be useful as a therapeutic agent. The drug must be administered intravenously , and may cause serious kidney toxicity. ACAM2000 is a smallpox vaccine developed by Acambis. It was approved for use in the United States by the U.S. FDA on August 31, 2007. It contains live vaccinia virus, cloned from the same strain used in an earlier vaccine , Dryvax . While the Dryvax virus was cultured in the skin of calves and freeze-dried, ACAM2000s virus is cultured in kidney epithelial cells ( Vero cells ) from an African green monkey . Efficacy and adverse reaction incidence are similar to Dryvax. The vaccine is not routinely available to the US public; it is, however, used in the military and maintained in the Strategic National Stockpile . In June 2021, brincidofovir was approved for medical use in the United States for the treatment of human smallpox disease caused by variola virus. The mortality rate from variola minor is approximately 1%, while the mortality rate from variola major is approximately 30%. Ordinary type-confluent is fatal about 50–75% of the time, ordinary-type semi-confluent about 25–50% of the time, in cases where the rash is discrete the case-fatality rate is less than 10%. The overall fatality rate for children younger than 1 year of age is 40–50%. Hemorrhagic and flat types have the highest fatality rates. The fatality rate for flat or late hemorrhagic type smallpox is 90% or greater and nearly 100% is observed in cases of early hemorrhagic smallpox. The case-fatality rate for variola minor is 1% or less. There is no evidence of chronic or recurrent infection with variola virus. In cases of flat smallpox in vaccinated people, the condition was extremely rare but less lethal, with one case series showing a 66.7% death rate. In fatal cases of ordinary smallpox, death usually occurs between days 10-16 of the illness. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. Circulating immune complexes , overwhelming viremia, or an uncontrolled immune response may be contributing factors. In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. The cause of death in early hemorrhagic cases is commonly due to heart failure and pulmonary edema . In late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often cited as causes of death. In flat smallpox modes of death are similar to those in burns, with loss of fluid , protein and electrolytes , and fulminating sepsis . Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia . Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated. Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, conjunctiva , and cornea , leading to complications such as conjunctivitis , keratitis , corneal ulcer , iritis , iridocyclitis , and atrophy of the optic nerve. Blindness results in approximately 35-40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2-5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa . Bony lesions are symmetrical, most common in the elbows, legs, and characteristically cause separation of the epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis , malformed bones, flail joints, and stubby fingers. Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face.Complications of smallpox arise most commonly in the respiratory system and range from simple bronchitis to fatal pneumonia . Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated. Other complications include encephalitis (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, conjunctiva , and cornea , leading to complications such as conjunctivitis , keratitis , corneal ulcer , iritis , iridocyclitis , and atrophy of the optic nerve. Blindness results in approximately 35-40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and retinal hemorrhages. In 2-5% of young children with smallpox, virions reach the joints and bone, causing osteomyelitis variolosa . Bony lesions are symmetrical, most common in the elbows, legs, and characteristically cause separation of the epiphysis and marked periosteal reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis , malformed bones, flail joints, and stubby fingers. Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face.The earliest credible clinical evidence of smallpox is found in the descriptions of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE), and China (1122 BCE), as well as a study of the Egyptian mummy of Ramses V , who died more than 3000 years ago (1145 BCE). It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BCE, where it remained as an endemic human disease for at least 2000 years. Smallpox was probably introduced into China during the 1st century CE from the southwest, and in the 6th century was carried from China to Japan. In Japan, the epidemic of 735–737 is believed to have killed as much as one-third of the population. At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion in West Africa. In India, the Hindu goddess of smallpox, Shitala , was worshipped in temples throughout the country. A different viewpoint is that smallpox emerged 1588 CE and the earlier reported cases were incorrectly identified as smallpox. The timing of the arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not clearly described in either the Old or New Testaments of the Bible or in the literature of the Greeks or Romans. While some have identified the Plague of Athens – which was said to have originated in " Ethiopia " and Egypt – or the plague that lifted Carthage's 396 BCE siege of Syracuse – with smallpox, many scholars agree it is very unlikely such a serious disease as variola major would have escaped being described by Hippocrates if it had existed in the Mediterranean region during his lifetime. While the Antonine Plague that swept through the Roman Empire in 165 – 180 CE may have been caused by smallpox, Saint Nicasius of Rheims became the patron saint of smallpox victims for having supposedly survived a bout in 450, and Saint Gregory of Tours recorded a similar outbreak in France and Italy in 580, the first use of the term variola . Other historians speculate that Arab armies first carried smallpox from Africa into Southwestern Europe during the 7th and 8th centuries. In the 9th century the Persian physician , Rhazes , provided one of the most definitive descriptions of smallpox and was the first to differentiate smallpox from measles and chickenpox in his Kitab fi al-jadari wa-al-hasbah ( The Book of Smallpox and Measles ). During the Middle Ages several smallpox outbreaks occurred in Europe. However, smallpox had not become established there until the population growth and mobility marked by the Crusades allowed it to do so. By the 16th century, smallpox had become entrenched across most of Europe, where it had a mortality rate as high as 30 percent. This endemic occurrence of smallpox in Europe is of particular historical importance, as successive exploration and colonization by Europeans tended to spread the disease to other nations. By the 16th century, smallpox had become a predominant cause of morbidity and mortality throughout much of the world. There were no credible descriptions of smallpox-like disease in the Americas before the westward exploration by Europeans in the 15th century CE. Smallpox was introduced into the Caribbean island of Hispaniola in 1507, and into the mainland in 1520, when Spanish settlers from Hispaniola arrived in Mexico, inadvertently carrying smallpox with them. Because the native Amerindian population had no acquired immunity to this new disease, their peoples were decimated by epidemics. Such disruption and population losses were an important factor in the Spanish achieving conquest of the Aztecs and the Incas . Similarly, English settlement of the east coast of North America in 1633 in Plymouth, Massachusetts was accompanied by devastating outbreaks of smallpox among Native American populations, and subsequently among the native-born colonists. Case fatality rates during outbreaks in Native American populations were as high as 90%. Smallpox was introduced into Australia in 1789 and again in 1829, though colonial surgeons, who by 1829 were attempting to distinguish between smallpox and chickenpox (which could be almost equally fatal to Aborigines), were divided as to whether the 1829–1830 epidemic was chickenpox or smallpox. Although smallpox was never endemic on the continent, it has been described as the principal cause of death in Aboriginal populations between 1780 and 1870. By the mid-18th century, smallpox was a major endemic disease everywhere in the world except in Australia and small islands untouched by outside exploration. In 18th century Europe, smallpox was a leading cause of death, killing an estimated 400,000 Europeans each year. Up to 10 percent of Swedish infants died of smallpox each year, and the death rate of infants in Russia might have been even higher. The widespread use of variolation in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. By the mid-20th century, variola minor occurred along with variola major, in varying proportions, in many parts of Africa. Patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. Infection with variola minor virus induces immunity against the more deadly variola major form. Thus, as variola minor spread all over the US, into Canada, the South American countries, and Great Britain, it became the dominant form of smallpox, further reducing mortality rates. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Dòuzhěn xīnfǎ ( 痘疹心法 , "Pox Rash Teachings") published in 1549, with earliest hints of the practice in China during the 10th century. In China, powdered smallpox scabs were blown up the noses of the healthy. People would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700: one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . Voltaire (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years". Variolation had also been witnessed in Turkey by Lady Mary Wortley Montagu , who later introduced it in the UK. An early mention of the possibility of smallpox's eradication was made in reference to the work of Johnnie Notions , a self-taught inoculator from Shetland , Scotland. Notions found success in treating people from at least the late 1780s through a method devised by himself despite having no formal medical background. His method involved exposing smallpox pus to peat smoke, burying it in the ground with camphor for up to 8 years, and then inserting the matter into a person's skin using a knife, and covering the incision with a cabbage leaf. He was reputed not to have lost a single patient. Arthur Edmondston , in writings on Notions' technique that were published in 1809, stated, "Had every practitioner been as uniformly successful in the disease as he was, the small-pox might have been banished from the face of the earth, without injuring the system, or leaving any doubt as to the fact." The English physician Edward Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, after which various attempts were made to eliminate smallpox on a regional scale. In Russia in 1796, the first child to receive this treatment was bestowed the name "Vaccinov" by Catherine the Great , and was educated at the expense of the nation. The introduction of the vaccine to the New World took place in Trinity, Newfoundland in 1800 by Dr. John Clinch , boyhood friend and medical colleague of Jenner. As early as 1803, the Spanish Crown organized the Balmis expedition to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there. The U.S. Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a robust state vaccination program existed in the Dutch East Indies . On August 26, 1807, Bavaria became the first country in the world to introduce compulsory vaccinations. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials. Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by indigenous preference for inoculation and distrust of vaccination, despite tough legislation, improvements in the local efficacy of the vaccine and vaccine preservative, and education efforts. By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans . In 1842, the United Kingdom banned inoculation, later progressing to mandatory vaccination . The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853. In the United States, from 1843 to 1855, first Massachusetts and then other states required smallpox vaccination. Although some disliked these measures, coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. In Northern Europe a number of countries had eliminated smallpox by 1900, and by 1914, the incidence in most industrialized countries had decreased to comparatively low levels. Vaccination continued in industrialized countries as protection against reintroduction until the mid to late 1970s. Australia and New Zealand are two notable exceptions; neither experienced endemic smallpox and never vaccinated widely, relying instead on protection by distance and strict quarantines. The first hemisphere -wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization . The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador. In 1958 Professor Viktor Zhdanov , Deputy Minister of Health for the USSR , called on the World Health Assembly to undertake a global initiative to eradicate smallpox. The proposal (Resolution WHA11.54) was accepted in 1959. At this point, 2 million people were dying from smallpox every year. Overall, the progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent . In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson . In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4 million annually to the effort, and adopted the new disease surveillance method promoted by Czech epidemiologist Karel Raška . In the early 1950s, an estimated 50 million cases of smallpox occurred in the world each year. To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. This process is known as "ring vaccination". The key to this strategy was the monitoring of cases in a community (known as surveillance) and containment. The initial problem the WHO team faced was inadequate reporting of smallpox cases, as many cases did not come to the attention of the authorities. The fact that humans are the only reservoir for smallpox infection and that carriers did not exist played a significant role in the eradication of smallpox. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. Early on, donations of vaccine were provided primarily by the Soviet Union and the United States, but by 1973, more than 80 percent of all vaccine was produced in developing countries. The Soviet Union provided one and a half billion doses between 1958 and 1979, as well as the medical staff. The last major European outbreak of smallpox was in 1972 in Yugoslavia , after a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus. The epidemic infected 175 people, causing 35 deaths. Authorities declared martial law , enforced quarantine, and undertook widespread re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over. Prior to this, there had been a smallpox outbreak in May–July 1963 in Stockholm , Sweden, brought from the Far East by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of the local population. By the end of 1975, smallpox persisted only in the Horn of Africa . Conditions were very difficult in Ethiopia and Somalia , where there were few roads. Civil war, famine, and refugees made the task even more difficult. An intensive surveillance, containment, and vaccination program was undertaken in these countries in early and mid-1977, under the direction of Australian microbiologist Frank Fenner . As the campaign neared its goal, Fenner and his team played an important role in verifying eradication. The last naturally occurring case of indigenous smallpox ( Variola minor ) was diagnosed in Ali Maow Maalin , a hospital cook in Merca, Somalia , on 26 October 1977. The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a three-year-old Bangladeshi girl, Rahima Banu . The global eradication of smallpox was certified, based on intense verification activities, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980. The first two sentences of the resolution read: Having considered the development and results of the global program on smallpox eradication initiated by WHO in 1958 and intensified since 1967 … Declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake and which only a decade ago was rampant in Africa, Asia and South America. The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence. The last case of smallpox in the world occurred in an outbreak in the United Kingdom in 1978 . A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978. Although it has remained unclear how Parker became infected, the source of the infection was established to be the variola virus grown for research purposes at the Medical School laboratory. All known stocks of smallpox worldwide were subsequently destroyed or transferred to two WHO-designated reference laboratories with BSL-4 facilities – the United States' Centers for Disease Control and Prevention (CDC) and the Soviet Union's (now Russia's) State Research Center of Virology and Biotechnology VECTOR . WHO first recommended destruction of the virus in 1986 and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999. Due to resistance from the U.S. and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes. Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak. Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests; a 2010 review by a team of public health experts appointed by WHO concluded that no essential public health purpose is served by the U.S. and Russia continuing to retain virus stocks. The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program. On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico . The envelope was labeled as containing scabs from a vaccination and gave scientists at the CDC an opportunity to study the history of smallpox vaccination in the United States. On July 1, 2014, six sealed glass vials of smallpox dated 1954, along with sample vials of other pathogens, were discovered in a cold storage room in an FDA laboratory at the National Institutes of Health location in Bethesda, Maryland . The smallpox vials were subsequently transferred to the custody of the CDC in Atlanta, where virus taken from at least two vials proved viable in culture. After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015. In 2017, scientists at the University of Alberta recreated an extinct horse pox virus to demonstrate that the variola virus can be recreated in a small lab at a cost of about $100,000, by a team of scientists without specialist knowledge. This makes the retention controversy irrelevant since the virus can be easily recreated even if all samples are destroyed. Although the scientists performed the research to help development of new vaccines as well as trace smallpox's history, the possibility of the techniques being used for nefarious purposes was immediately recognized, raising questions on dual use research and regulations. In September 2019, the Russian lab housing smallpox samples experienced a gas explosion that injured one worker. It did not occur near the virus storage area, and no samples were compromised, but the incident prompted a review of risks to containment. The earliest credible clinical evidence of smallpox is found in the descriptions of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE), and China (1122 BCE), as well as a study of the Egyptian mummy of Ramses V , who died more than 3000 years ago (1145 BCE). It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BCE, where it remained as an endemic human disease for at least 2000 years. Smallpox was probably introduced into China during the 1st century CE from the southwest, and in the 6th century was carried from China to Japan. In Japan, the epidemic of 735–737 is believed to have killed as much as one-third of the population. At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the Yoruba religion in West Africa. In India, the Hindu goddess of smallpox, Shitala , was worshipped in temples throughout the country. A different viewpoint is that smallpox emerged 1588 CE and the earlier reported cases were incorrectly identified as smallpox. The timing of the arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not clearly described in either the Old or New Testaments of the Bible or in the literature of the Greeks or Romans. While some have identified the Plague of Athens – which was said to have originated in " Ethiopia " and Egypt – or the plague that lifted Carthage's 396 BCE siege of Syracuse – with smallpox, many scholars agree it is very unlikely such a serious disease as variola major would have escaped being described by Hippocrates if it had existed in the Mediterranean region during his lifetime. While the Antonine Plague that swept through the Roman Empire in 165 – 180 CE may have been caused by smallpox, Saint Nicasius of Rheims became the patron saint of smallpox victims for having supposedly survived a bout in 450, and Saint Gregory of Tours recorded a similar outbreak in France and Italy in 580, the first use of the term variola . Other historians speculate that Arab armies first carried smallpox from Africa into Southwestern Europe during the 7th and 8th centuries. In the 9th century the Persian physician , Rhazes , provided one of the most definitive descriptions of smallpox and was the first to differentiate smallpox from measles and chickenpox in his Kitab fi al-jadari wa-al-hasbah ( The Book of Smallpox and Measles ). During the Middle Ages several smallpox outbreaks occurred in Europe. However, smallpox had not become established there until the population growth and mobility marked by the Crusades allowed it to do so. By the 16th century, smallpox had become entrenched across most of Europe, where it had a mortality rate as high as 30 percent. This endemic occurrence of smallpox in Europe is of particular historical importance, as successive exploration and colonization by Europeans tended to spread the disease to other nations. By the 16th century, smallpox had become a predominant cause of morbidity and mortality throughout much of the world. There were no credible descriptions of smallpox-like disease in the Americas before the westward exploration by Europeans in the 15th century CE. Smallpox was introduced into the Caribbean island of Hispaniola in 1507, and into the mainland in 1520, when Spanish settlers from Hispaniola arrived in Mexico, inadvertently carrying smallpox with them. Because the native Amerindian population had no acquired immunity to this new disease, their peoples were decimated by epidemics. Such disruption and population losses were an important factor in the Spanish achieving conquest of the Aztecs and the Incas . Similarly, English settlement of the east coast of North America in 1633 in Plymouth, Massachusetts was accompanied by devastating outbreaks of smallpox among Native American populations, and subsequently among the native-born colonists. Case fatality rates during outbreaks in Native American populations were as high as 90%. Smallpox was introduced into Australia in 1789 and again in 1829, though colonial surgeons, who by 1829 were attempting to distinguish between smallpox and chickenpox (which could be almost equally fatal to Aborigines), were divided as to whether the 1829–1830 epidemic was chickenpox or smallpox. Although smallpox was never endemic on the continent, it has been described as the principal cause of death in Aboriginal populations between 1780 and 1870. By the mid-18th century, smallpox was a major endemic disease everywhere in the world except in Australia and small islands untouched by outside exploration. In 18th century Europe, smallpox was a leading cause of death, killing an estimated 400,000 Europeans each year. Up to 10 percent of Swedish infants died of smallpox each year, and the death rate of infants in Russia might have been even higher. The widespread use of variolation in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. By the mid-20th century, variola minor occurred along with variola major, in varying proportions, in many parts of Africa. Patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. Infection with variola minor virus induces immunity against the more deadly variola major form. Thus, as variola minor spread all over the US, into Canada, the South American countries, and Great Britain, it became the dominant form of smallpox, further reducing mortality rates. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Dòuzhěn xīnfǎ ( 痘疹心法 , "Pox Rash Teachings") published in 1549, with earliest hints of the practice in China during the 10th century. In China, powdered smallpox scabs were blown up the noses of the healthy. People would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700: one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . Voltaire (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years". Variolation had also been witnessed in Turkey by Lady Mary Wortley Montagu , who later introduced it in the UK. An early mention of the possibility of smallpox's eradication was made in reference to the work of Johnnie Notions , a self-taught inoculator from Shetland , Scotland. Notions found success in treating people from at least the late 1780s through a method devised by himself despite having no formal medical background. His method involved exposing smallpox pus to peat smoke, burying it in the ground with camphor for up to 8 years, and then inserting the matter into a person's skin using a knife, and covering the incision with a cabbage leaf. He was reputed not to have lost a single patient. Arthur Edmondston , in writings on Notions' technique that were published in 1809, stated, "Had every practitioner been as uniformly successful in the disease as he was, the small-pox might have been banished from the face of the earth, without injuring the system, or leaving any doubt as to the fact." The English physician Edward Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, after which various attempts were made to eliminate smallpox on a regional scale. In Russia in 1796, the first child to receive this treatment was bestowed the name "Vaccinov" by Catherine the Great , and was educated at the expense of the nation. The introduction of the vaccine to the New World took place in Trinity, Newfoundland in 1800 by Dr. John Clinch , boyhood friend and medical colleague of Jenner. As early as 1803, the Spanish Crown organized the Balmis expedition to transport the vaccine to the Spanish colonies in the Americas and the Philippines, and establish mass vaccination programs there. The U.S. Congress passed the Vaccine Act of 1813 to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a robust state vaccination program existed in the Dutch East Indies . On August 26, 1807, Bavaria became the first country in the world to introduce compulsory vaccinations. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials. Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by indigenous preference for inoculation and distrust of vaccination, despite tough legislation, improvements in the local efficacy of the vaccine and vaccine preservative, and education efforts. By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans . In 1842, the United Kingdom banned inoculation, later progressing to mandatory vaccination . The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853. In the United States, from 1843 to 1855, first Massachusetts and then other states required smallpox vaccination. Although some disliked these measures, coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. In Northern Europe a number of countries had eliminated smallpox by 1900, and by 1914, the incidence in most industrialized countries had decreased to comparatively low levels. Vaccination continued in industrialized countries as protection against reintroduction until the mid to late 1970s. Australia and New Zealand are two notable exceptions; neither experienced endemic smallpox and never vaccinated widely, relying instead on protection by distance and strict quarantines. The first hemisphere -wide effort to eradicate smallpox was made in 1950 by the Pan American Health Organization . The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador. In 1958 Professor Viktor Zhdanov , Deputy Minister of Health for the USSR , called on the World Health Assembly to undertake a global initiative to eradicate smallpox. The proposal (Resolution WHA11.54) was accepted in 1959. At this point, 2 million people were dying from smallpox every year. Overall, the progress towards eradication was disappointing, especially in Africa and in the Indian subcontinent . In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson . In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4 million annually to the effort, and adopted the new disease surveillance method promoted by Czech epidemiologist Karel Raška . In the early 1950s, an estimated 50 million cases of smallpox occurred in the world each year. To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by. This process is known as "ring vaccination". The key to this strategy was the monitoring of cases in a community (known as surveillance) and containment. The initial problem the WHO team faced was inadequate reporting of smallpox cases, as many cases did not come to the attention of the authorities. The fact that humans are the only reservoir for smallpox infection and that carriers did not exist played a significant role in the eradication of smallpox. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. Early on, donations of vaccine were provided primarily by the Soviet Union and the United States, but by 1973, more than 80 percent of all vaccine was produced in developing countries. The Soviet Union provided one and a half billion doses between 1958 and 1979, as well as the medical staff. The last major European outbreak of smallpox was in 1972 in Yugoslavia , after a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus. The epidemic infected 175 people, causing 35 deaths. Authorities declared martial law , enforced quarantine, and undertook widespread re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over. Prior to this, there had been a smallpox outbreak in May–July 1963 in Stockholm , Sweden, brought from the Far East by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of the local population. By the end of 1975, smallpox persisted only in the Horn of Africa . Conditions were very difficult in Ethiopia and Somalia , where there were few roads. Civil war, famine, and refugees made the task even more difficult. An intensive surveillance, containment, and vaccination program was undertaken in these countries in early and mid-1977, under the direction of Australian microbiologist Frank Fenner . As the campaign neared its goal, Fenner and his team played an important role in verifying eradication. The last naturally occurring case of indigenous smallpox ( Variola minor ) was diagnosed in Ali Maow Maalin , a hospital cook in Merca, Somalia , on 26 October 1977. The last naturally occurring case of the more deadly Variola major had been detected in October 1975 in a three-year-old Bangladeshi girl, Rahima Banu . The global eradication of smallpox was certified, based on intense verification activities, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980. The first two sentences of the resolution read: Having considered the development and results of the global program on smallpox eradication initiated by WHO in 1958 and intensified since 1967 … Declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake and which only a decade ago was rampant in Africa, Asia and South America. The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence. The cost of the eradication effort, from 1967 to 1979, was roughly US$300 million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence. The last case of smallpox in the world occurred in an outbreak in the United Kingdom in 1978 . A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978. Although it has remained unclear how Parker became infected, the source of the infection was established to be the variola virus grown for research purposes at the Medical School laboratory. All known stocks of smallpox worldwide were subsequently destroyed or transferred to two WHO-designated reference laboratories with BSL-4 facilities – the United States' Centers for Disease Control and Prevention (CDC) and the Soviet Union's (now Russia's) State Research Center of Virology and Biotechnology VECTOR . WHO first recommended destruction of the virus in 1986 and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999. Due to resistance from the U.S. and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes. Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak. Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests; a 2010 review by a team of public health experts appointed by WHO concluded that no essential public health purpose is served by the U.S. and Russia continuing to retain virus stocks. The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program. On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico . The envelope was labeled as containing scabs from a vaccination and gave scientists at the CDC an opportunity to study the history of smallpox vaccination in the United States. On July 1, 2014, six sealed glass vials of smallpox dated 1954, along with sample vials of other pathogens, were discovered in a cold storage room in an FDA laboratory at the National Institutes of Health location in Bethesda, Maryland . The smallpox vials were subsequently transferred to the custody of the CDC in Atlanta, where virus taken from at least two vials proved viable in culture. After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015. In 2017, scientists at the University of Alberta recreated an extinct horse pox virus to demonstrate that the variola virus can be recreated in a small lab at a cost of about $100,000, by a team of scientists without specialist knowledge. This makes the retention controversy irrelevant since the virus can be easily recreated even if all samples are destroyed. Although the scientists performed the research to help development of new vaccines as well as trace smallpox's history, the possibility of the techniques being used for nefarious purposes was immediately recognized, raising questions on dual use research and regulations. In September 2019, the Russian lab housing smallpox samples experienced a gas explosion that injured one worker. It did not occur near the virus storage area, and no samples were compromised, but the incident prompted a review of risks to containment. In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region. A group of Native American warriors laid siege to British-held Fort Pitt on June 22. In response, Henry Bouquet , the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, Sir Jeffrey Amherst , who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate [ sic ] the Indians by means of Blankets that may fall in their hands". On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783). According to a theory put forward in Journal of Australian Studies ( JAS ) by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales . This theory was also considered earlier in Bulletin of the History of Medicine and by David Day. However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of chickenpox —a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it. Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the JAS article that the likely source was bottles of variola virus possessed by First Fleet surgeons . Ian and Jennifer Glynn, in The life and death of smallpox , confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789. In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable. However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin. W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population. However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis. In a 2013 lecture at the Australian National University, Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all c. 18th century (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons … would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox." During World War II , scientists from the United Kingdom, United States, and Japan ( Unit 731 of the Imperial Japanese Army ) were involved in research into producing a biological weapon from smallpox. Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine . In 1947, the Soviet Union established a smallpox weapons factory in the city of Zagorsk , 75 km to the northeast of Moscow. An outbreak of weaponized smallpox occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons , described the incident: On Vozrozhdeniya Island in the Aral Sea , the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk . A research ship of the Aral fleet came to within 15 km of the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation – 400 gr. of which was exploded on the island – "got her" and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of the Ministry of Defense and requested to forbid the stop of the Alma-Ata –Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov , who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island. Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt , two cities where the boat docked. Responding to international pressures, in 1991 the Soviet government allowed a joint U.S.–British inspection team to tour four of its main weapons facilities at Biopreparat . The inspectors were met with evasion and denials from the Soviet scientists and were eventually ordered out of the facility. In 1992, Soviet defector Ken Alibek alleged that the Soviet bioweapons program at Zagorsk had produced a large stockpile – as much as twenty tons – of weaponized smallpox (possibly engineered to resist vaccines, Alibek further alleged), along with refrigerated warheads to deliver it. Alibek's stories about the former Soviet program's smallpox activities have never been independently verified. In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo . With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, U.S. government officials have expressed concern that smallpox and the expertise to weaponize it may have become available to other governments or terrorist groups who might wish to use virus as means of biological warfare. Specific allegations made against Iraq in this respect proved to be false. Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull , Ramses V , the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor of China, Emperor Komei of Japan (died of smallpox in 1867), and Date Masamune of Japan (who lost an eye to the disease). Cuitláhuac , the 10th tlatoani (ruler) of the Aztec city of Tenochtitlan , died of smallpox in 1520, shortly after its introduction to the Americas , and the Incan emperor Huayna Capac died of it in 1527 (causing a civil war of succession in the Inca empire and the eventual conquest by the Spaniards). More recent public figures include Guru Har Krishan , 8th Guru of the Sikhs, in 1664, Louis I of Spain in 1724 (died), Peter II of Russia in 1730 (died), George Washington (survived), Louis XV of France in 1774 (died) and Maximilian III Joseph of Bavaria in 1777 (died). Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of Henry VIII of England survived the disease but were scarred by it. These include his sister Margaret , his wife Anne of Cleves , and his two daughters: Mary I in 1527 and Elizabeth I in 1562. Elizabeth tried to disguise the pockmarks with heavy makeup. Mary, Queen of Scots , contracted the disease as a child but had no visible scarring. In Europe, deaths from smallpox often changed dynastic succession. Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those higher in the succession line. He himself died of the disease in 1774. Peter II of Russia died of the disease at 14 years of age. Also, before becoming emperor, Peter III of Russia caught the virus and suffered greatly from it. [ citation needed ] He was left scarred and disfigured. His wife, Catherine the Great , was spared but fear of the virus clearly had its effects on her. She feared for the safety of her son, Paul , so much that she made sure that large crowds were kept at bay and sought to isolate him. Eventually, she decided to have herself inoculated by a British doctor, Thomas Dimsdale . While this was considered a controversial method at the time, she succeeded. Paul was later inoculated as well. Catherine then sought to have inoculations throughout her empire stating: "My objective was, through my example, to save from death the multitude of my subjects who, not knowing the value of this technique, and frightened of it, were left in danger." By 1800, approximately two million inoculations had been administered in the Russian Empire. In China, the Qing dynasty had extensive protocols to protect Manchus from Peking 's endemic smallpox. U.S. Presidents George Washington , Andrew Jackson , and Abraham Lincoln all contracted and recovered from the disease. Washington became infected with smallpox on a visit to Barbados in 1751. Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not. Lincoln contracted the disease during his presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863. The famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation. Soviet leader Joseph Stalin fell ill with smallpox at the age of seven. His face was badly scarred by the disease. He later had photographs retouched to make his pockmarks less apparent. Hungarian poet Ferenc Kölcsey , who wrote the Hungarian national anthem, lost his right eye to smallpox. In the face of the devastation of smallpox, various smallpox gods and goddesses have been worshipped throughout parts of the Old World , for example in China and India. In China, the smallpox goddess was referred to as T'ou-Shen Niang-Niang ( Chinese : 痘疹娘娘 ). Chinese believers actively worked to appease the goddess and pray for her mercy, by such measures as referring to smallpox pustules as "beautiful flowers" as a euphemism intended to avert offending the goddess, for example (the Chinese word for smallpox is 天花 , literally "heaven flower"). In a related New Year's Eve custom it was prescribed that the children of the house wear ugly masks while sleeping, so as to conceal any beauty and thereby avoid attracting the goddess, who would be passing through sometime that night. If a case of smallpox did occur, shrines would be set up in the homes of the victims, to be worshipped and offered to as the disease ran its course. If the victim recovered, the shrines were removed and carried away in a special paper chair or boat for burning. If the patient did not recover, the shrine was destroyed and cursed, to expel the goddess from the house. In the Yoruba language smallpox is known as ṣọpọná, but it was also written as shakpanna, shopona, ṣhapana, and ṣọpọnọ. The word is a combination of 3 words, the verb ṣán, meaning to cover or plaster (referring to the pustules characteristic of smallpox), kpa or pa, meaning to kill, and enia, meaning human. Roughly translated, it means One who kills a person by covering them with pustules. Among the Yorùbá people of West Africa, and also in Dahomean religion , Trinidad, and in Brazil , The deity Sopona , also known as Obaluaye , is the deity of smallpox and other deadly diseases (like leprosy, HIV/AIDS, and fevers). One of the most feared deities of the orisha pantheon, smallpox was seen as a form of punishment from Shopona. Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered. However, Shopona was also seen as a healer who could cure the diseases he inflicted, and he was often called upon by his victims to heal them. The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents. India's first records of smallpox can be found in a medical book that dates back to 400 CE. This book describes a disease that sounds exceptionally like smallpox. India, like China and the Yorùbá, created a goddess in response to its exposure to smallpox. The Hindu goddess Shitala was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already affected. Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe patients. Shrines were created where many Indian natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala, placed plates of cooling foods and pots of water on the roofs of their homes. In cultures that did not recognize a smallpox deity, there was often nonetheless a belief in smallpox demons , who were accordingly blamed for the disease. Such beliefs were prominent in Japan, Europe, Africa, and other parts of the world. Nearly all cultures who believed in the demon also believed that it was afraid of the color red. This led to the invention of the so-called red treatment, where patients and their rooms would be decorated in red. The practice spread to Europe in the 12th century and was practiced by (among others) Charles V of France and Elizabeth I of England . Afforded scientific credibility through the studies by Niels Ryberg Finsen showing that red light reduced scarring, this belief persisted even until the 1930s.In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region. A group of Native American warriors laid siege to British-held Fort Pitt on June 22. In response, Henry Bouquet , the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, Sir Jeffrey Amherst , who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate [ sic ] the Indians by means of Blankets that may fall in their hands". On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783). According to a theory put forward in Journal of Australian Studies ( JAS ) by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales . This theory was also considered earlier in Bulletin of the History of Medicine and by David Day. However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of chickenpox —a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it. Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the JAS article that the likely source was bottles of variola virus possessed by First Fleet surgeons . Ian and Jennifer Glynn, in The life and death of smallpox , confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789. In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable. However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin. W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population. However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis. In a 2013 lecture at the Australian National University, Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all c. 18th century (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons … would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox." During World War II , scientists from the United Kingdom, United States, and Japan ( Unit 731 of the Imperial Japanese Army ) were involved in research into producing a biological weapon from smallpox. Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a vaccine . In 1947, the Soviet Union established a smallpox weapons factory in the city of Zagorsk , 75 km to the northeast of Moscow. An outbreak of weaponized smallpox occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons , described the incident: On Vozrozhdeniya Island in the Aral Sea , the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk . A research ship of the Aral fleet came to within 15 km of the island (it was forbidden to come any closer than 40 km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation – 400 gr. of which was exploded on the island – "got her" and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of the Ministry of Defense and requested to forbid the stop of the Alma-Ata –Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov , who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island. Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt , two cities where the boat docked. Responding to international pressures, in 1991 the Soviet government allowed a joint U.S.–British inspection team to tour four of its main weapons facilities at Biopreparat . The inspectors were met with evasion and denials from the Soviet scientists and were eventually ordered out of the facility. In 1992, Soviet defector Ken Alibek alleged that the Soviet bioweapons program at Zagorsk had produced a large stockpile – as much as twenty tons – of weaponized smallpox (possibly engineered to resist vaccines, Alibek further alleged), along with refrigerated warheads to deliver it. Alibek's stories about the former Soviet program's smallpox activities have never been independently verified. In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo . With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, U.S. government officials have expressed concern that smallpox and the expertise to weaponize it may have become available to other governments or terrorist groups who might wish to use virus as means of biological warfare. Specific allegations made against Iraq in this respect proved to be false. Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull , Ramses V , the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor of China, Emperor Komei of Japan (died of smallpox in 1867), and Date Masamune of Japan (who lost an eye to the disease). Cuitláhuac , the 10th tlatoani (ruler) of the Aztec city of Tenochtitlan , died of smallpox in 1520, shortly after its introduction to the Americas , and the Incan emperor Huayna Capac died of it in 1527 (causing a civil war of succession in the Inca empire and the eventual conquest by the Spaniards). More recent public figures include Guru Har Krishan , 8th Guru of the Sikhs, in 1664, Louis I of Spain in 1724 (died), Peter II of Russia in 1730 (died), George Washington (survived), Louis XV of France in 1774 (died) and Maximilian III Joseph of Bavaria in 1777 (died). Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of Henry VIII of England survived the disease but were scarred by it. These include his sister Margaret , his wife Anne of Cleves , and his two daughters: Mary I in 1527 and Elizabeth I in 1562. Elizabeth tried to disguise the pockmarks with heavy makeup. Mary, Queen of Scots , contracted the disease as a child but had no visible scarring. In Europe, deaths from smallpox often changed dynastic succession. Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those higher in the succession line. He himself died of the disease in 1774. Peter II of Russia died of the disease at 14 years of age. Also, before becoming emperor, Peter III of Russia caught the virus and suffered greatly from it. [ citation needed ] He was left scarred and disfigured. His wife, Catherine the Great , was spared but fear of the virus clearly had its effects on her. She feared for the safety of her son, Paul , so much that she made sure that large crowds were kept at bay and sought to isolate him. Eventually, she decided to have herself inoculated by a British doctor, Thomas Dimsdale . While this was considered a controversial method at the time, she succeeded. Paul was later inoculated as well. Catherine then sought to have inoculations throughout her empire stating: "My objective was, through my example, to save from death the multitude of my subjects who, not knowing the value of this technique, and frightened of it, were left in danger." By 1800, approximately two million inoculations had been administered in the Russian Empire. In China, the Qing dynasty had extensive protocols to protect Manchus from Peking 's endemic smallpox. U.S. Presidents George Washington , Andrew Jackson , and Abraham Lincoln all contracted and recovered from the disease. Washington became infected with smallpox on a visit to Barbados in 1751. Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not. Lincoln contracted the disease during his presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863. The famous theologian Jonathan Edwards died of smallpox in 1758 following an inoculation. Soviet leader Joseph Stalin fell ill with smallpox at the age of seven. His face was badly scarred by the disease. He later had photographs retouched to make his pockmarks less apparent. Hungarian poet Ferenc Kölcsey , who wrote the Hungarian national anthem, lost his right eye to smallpox. In the face of the devastation of smallpox, various smallpox gods and goddesses have been worshipped throughout parts of the Old World , for example in China and India. In China, the smallpox goddess was referred to as T'ou-Shen Niang-Niang ( Chinese : 痘疹娘娘 ). Chinese believers actively worked to appease the goddess and pray for her mercy, by such measures as referring to smallpox pustules as "beautiful flowers" as a euphemism intended to avert offending the goddess, for example (the Chinese word for smallpox is 天花 , literally "heaven flower"). In a related New Year's Eve custom it was prescribed that the children of the house wear ugly masks while sleeping, so as to conceal any beauty and thereby avoid attracting the goddess, who would be passing through sometime that night. If a case of smallpox did occur, shrines would be set up in the homes of the victims, to be worshipped and offered to as the disease ran its course. If the victim recovered, the shrines were removed and carried away in a special paper chair or boat for burning. If the patient did not recover, the shrine was destroyed and cursed, to expel the goddess from the house. In the Yoruba language smallpox is known as ṣọpọná, but it was also written as shakpanna, shopona, ṣhapana, and ṣọpọnọ. The word is a combination of 3 words, the verb ṣán, meaning to cover or plaster (referring to the pustules characteristic of smallpox), kpa or pa, meaning to kill, and enia, meaning human. Roughly translated, it means One who kills a person by covering them with pustules. Among the Yorùbá people of West Africa, and also in Dahomean religion , Trinidad, and in Brazil , The deity Sopona , also known as Obaluaye , is the deity of smallpox and other deadly diseases (like leprosy, HIV/AIDS, and fevers). One of the most feared deities of the orisha pantheon, smallpox was seen as a form of punishment from Shopona. Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered. However, Shopona was also seen as a healer who could cure the diseases he inflicted, and he was often called upon by his victims to heal them. The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents. India's first records of smallpox can be found in a medical book that dates back to 400 CE. This book describes a disease that sounds exceptionally like smallpox. India, like China and the Yorùbá, created a goddess in response to its exposure to smallpox. The Hindu goddess Shitala was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already affected. Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe patients. Shrines were created where many Indian natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala, placed plates of cooling foods and pots of water on the roofs of their homes. In cultures that did not recognize a smallpox deity, there was often nonetheless a belief in smallpox demons , who were accordingly blamed for the disease. Such beliefs were prominent in Japan, Europe, Africa, and other parts of the world. Nearly all cultures who believed in the demon also believed that it was afraid of the color red. This led to the invention of the so-called red treatment, where patients and their rooms would be decorated in red. The practice spread to Europe in the 12th century and was practiced by (among others) Charles V of France and Elizabeth I of England . Afforded scientific credibility through the studies by Niels Ryberg Finsen showing that red light reduced scarring, this belief persisted even until the 1930s.

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Emergent BioSolutions

Emergent BioSolutions Inc. is an American multinational specialty biopharmaceutical company headquartered in Gaithersburg, Maryland. It develops vaccines and antibody therapeutics for infectious diseases and opioid overdoses, and it provides medical devices for biodefense purposes. Among the company's products are the controversial BioThrax (Anthrax Vaccine Adsorbed), the only anthrax vaccine licensed by the U.S. Food and Drug Administration (FDA) and Narcan ( naloxone ) for the emergency treatment of opioid overdose. The company also manufactures pharmaceuticals for infectious diseases like cholera and typhoid. During the COVID-19 pandemic , Emergent BioSolutions also produced Johnson & Johnson/Janssen and Oxford–AstraZeneca vaccines at one of its plants; however, this was marked by contamination and other production issues, and millions of doses of vaccine had to be discarded.Emergent BioSolutions was founded on September 5, 1998, by Fuad El-Hibri , under the name BioPort, which had formerly operated as a state-owned entity named Michigan Biological Products Institute and was privatized as Emergent BioSolutions in 2004. At the time, the Michigan Department of Public Health , though its Michigan Biologics Products Institute, owned an anthrax vaccine manufacturing facility in Lansing, Michigan . BioPort purchased the facility and the rights to manufacture the vaccine for the U.S. military. In 2000, operating as Bioport, the company was the subject of Congressional hearings and FDA action (official action indicated (OAI) and voluntary action indicated (VAI)). After the 2001 anthrax attacks that caused the deaths of five Americans and made 17 others ill, Bioport began providing its anthrax vaccine to US biodefense agencies. Emergent became a publicly traded company in 2006, with its stock trading on the New York Stock Exchange under the symbol EBS. In June 2012, Emergent, along with Novartis and the Texas A&M University System was selected by the U.S. Department of Health and Human Services as one of the three Centers for Innovation in Advanced Development and Manufacturing. The public-private partnership granted Emergent $163 million over eight years to assist in the development of countermeasures for health, nuclear and radiological epidemics. The purpose is to produce medical countermeasures in the event of a national pandemic. Emergent's facility is located in Maryland and the company expects the site to be operational by the year 2020. The company purchased Winnipeg, Manitoba's Cangene Corporation in 2013. Cangene's leading product is WinRho, which treats the blood disease immune thrombocytopenic purpura, as well as hemolytic disease of the newborn. Cangene also produces pharmaceuticals that treat Hepatitis B and varicella (chickenpox). On June 27, 2016, the US Biomedical Advanced Research and Development Authority contracted with Emergent Biosolutions to develop a vaccine for the Zika virus . The contract was spread out over 30 months and was worth around $22 million. The vaccine was projected to reach stage-one clinical trials by early 2017. As of the end of June 2016, 60 countries and territories had reported transmission of the Zika virus from mosquitoes. Emergent was one of the first companies to develop a vaccine for the virus. Emergent spun off its biosciences division in August 2016, forming a new company, Aptevo Therapeutics in Seattle, WA. The new company continues its focus on developing treatments for cancer and blood diseases using its technology of dual-ended molecules that assault cancer cells, each end attacking the cancer in a different way. Aptevo had four products available at its inception. In December 2016, Health Canada approved the purchase of Emergent's new botulism antitoxin called Botulism Antitoxin Heptavalent (BAT). The CDC and Public Health Agency of Canada both identified botulism, a type of food poisoning , as a likely biological threat. Emergent already has a ten-year contract with the Canadian military and national health service to supply BAT that began in 2012. Emergent also provides BAT to the U.S. Strategic National Stockpile . BAT was first licensed in the U.S. in 2013 and is the only botulism antitoxin available in the U.S. for naturally-occurring cases of non-infant botulism. On March 31, 2017, Emergent signed a modification to its contract with BARDA to "manufacture and store bulk drug substance for its botulism antitoxin, BAT." The contract is valued at approximately $53 million for five years. The contract modification was technical in nature; it allows Emergent to file and deliver the final drug product to the Strategic National Stockpile in the future. Soligenix Inc. and Emergent agreed to establish a "commercially viable production technology" for the development of RiVax, a potential vaccine aimed to protect against ricin exposure. Currently, there are no treatments for ricin poisoning that have been proven effective. Soligenix is a late-stage biopharmaceutical company that specializes in the development of treatments for rare diseases. A product of castor oil production, the ricin toxin can be a useful biological weapon due to its extreme potency, stability, and accessibility. The National Institute of Allergy and Infectious Diseases funded the development of RiVax costing an estimated $24.7 million. The organization also financially backed the contract between Emergent and Soligenix. Most of the work was conducted in Baltimore, Maryland, at Emergent's manufacturing facility. An expansion of the Baltimore plant, finished in 2017, had $163 million in funding from the U.S. government. In January 2020, Emergent informed Soligenix of manufacturing issues, having provided doses of RiVax that were "out of specification", causing the study to be suspended even after two trial participants had received doses. In April 2020, the Department of Health and Human Services announced that it would not provide further funding for RiVax clinical trials, although the agency did not announce whether this was related to previous issues. In subsequent securities filings, Soligenix stated that it was pursuing $19 million in damages from Emergent in arbitration proceedings. In 2017, the company purchased the ACAM2000 (smallpox vaccinia) Vaccine, the only FDA-approved (2007)vaccine for active immunization against smallpox for those at a medical high risk of contracting the disease, from Sanofi Pasteur. Two years later, the Office of the Assistant Secretary for Preparedness and Response , Department of Health and Human Services, has signed a contract with the company worth an estimated US$2.8 billion for the company to provide ACAM2000 over a ten-year period. In 2018, Emergent acquired Adapt Pharma, the manufacturer of Narcan ( naloxone ), a widely used nasal spray opioid-overdose antidote, for $735 million. Adapt is headquartered in Dublin, Ireland, and operates from Radnor, PA. Emergent purchased (also in 2018) the specialty vaccine manufacturer PaxVax, whose product line includes FDA-approved typhoid vaccine Vivotif and cholera vaccine Vaxchora, from its owner, Cerebus Capital Management, a private equity fund. Vaxchora is the only oral vaccine against cholera approved by the FDA in the US. The acquisition also includes rights to vaccines in development. One of these vaccines is being tested as a prophylactic against the acute-respiratory disease adenovirus. Another is focused on the chikungunya virus which is transmitted by mosquitoes. The transaction provides Emergent with a Swiss R&D facility. Emergent BioSolutions was founded on September 5, 1998, by Fuad El-Hibri , under the name BioPort, which had formerly operated as a state-owned entity named Michigan Biological Products Institute and was privatized as Emergent BioSolutions in 2004. At the time, the Michigan Department of Public Health , though its Michigan Biologics Products Institute, owned an anthrax vaccine manufacturing facility in Lansing, Michigan . BioPort purchased the facility and the rights to manufacture the vaccine for the U.S. military. In 2000, operating as Bioport, the company was the subject of Congressional hearings and FDA action (official action indicated (OAI) and voluntary action indicated (VAI)). After the 2001 anthrax attacks that caused the deaths of five Americans and made 17 others ill, Bioport began providing its anthrax vaccine to US biodefense agencies. Emergent became a publicly traded company in 2006, with its stock trading on the New York Stock Exchange under the symbol EBS. In June 2012, Emergent, along with Novartis and the Texas A&M University System was selected by the U.S. Department of Health and Human Services as one of the three Centers for Innovation in Advanced Development and Manufacturing. The public-private partnership granted Emergent $163 million over eight years to assist in the development of countermeasures for health, nuclear and radiological epidemics. The purpose is to produce medical countermeasures in the event of a national pandemic. Emergent's facility is located in Maryland and the company expects the site to be operational by the year 2020. The company purchased Winnipeg, Manitoba's Cangene Corporation in 2013. Cangene's leading product is WinRho, which treats the blood disease immune thrombocytopenic purpura, as well as hemolytic disease of the newborn. Cangene also produces pharmaceuticals that treat Hepatitis B and varicella (chickenpox). On June 27, 2016, the US Biomedical Advanced Research and Development Authority contracted with Emergent Biosolutions to develop a vaccine for the Zika virus . The contract was spread out over 30 months and was worth around $22 million. The vaccine was projected to reach stage-one clinical trials by early 2017. As of the end of June 2016, 60 countries and territories had reported transmission of the Zika virus from mosquitoes. Emergent was one of the first companies to develop a vaccine for the virus. Emergent spun off its biosciences division in August 2016, forming a new company, Aptevo Therapeutics in Seattle, WA. The new company continues its focus on developing treatments for cancer and blood diseases using its technology of dual-ended molecules that assault cancer cells, each end attacking the cancer in a different way. Aptevo had four products available at its inception. In December 2016, Health Canada approved the purchase of Emergent's new botulism antitoxin called Botulism Antitoxin Heptavalent (BAT). The CDC and Public Health Agency of Canada both identified botulism, a type of food poisoning , as a likely biological threat. Emergent already has a ten-year contract with the Canadian military and national health service to supply BAT that began in 2012. Emergent also provides BAT to the U.S. Strategic National Stockpile . BAT was first licensed in the U.S. in 2013 and is the only botulism antitoxin available in the U.S. for naturally-occurring cases of non-infant botulism. On March 31, 2017, Emergent signed a modification to its contract with BARDA to "manufacture and store bulk drug substance for its botulism antitoxin, BAT." The contract is valued at approximately $53 million for five years. The contract modification was technical in nature; it allows Emergent to file and deliver the final drug product to the Strategic National Stockpile in the future. Soligenix Inc. and Emergent agreed to establish a "commercially viable production technology" for the development of RiVax, a potential vaccine aimed to protect against ricin exposure. Currently, there are no treatments for ricin poisoning that have been proven effective. Soligenix is a late-stage biopharmaceutical company that specializes in the development of treatments for rare diseases. A product of castor oil production, the ricin toxin can be a useful biological weapon due to its extreme potency, stability, and accessibility. The National Institute of Allergy and Infectious Diseases funded the development of RiVax costing an estimated $24.7 million. The organization also financially backed the contract between Emergent and Soligenix. Most of the work was conducted in Baltimore, Maryland, at Emergent's manufacturing facility. An expansion of the Baltimore plant, finished in 2017, had $163 million in funding from the U.S. government. In January 2020, Emergent informed Soligenix of manufacturing issues, having provided doses of RiVax that were "out of specification", causing the study to be suspended even after two trial participants had received doses. In April 2020, the Department of Health and Human Services announced that it would not provide further funding for RiVax clinical trials, although the agency did not announce whether this was related to previous issues. In subsequent securities filings, Soligenix stated that it was pursuing $19 million in damages from Emergent in arbitration proceedings. In 2017, the company purchased the ACAM2000 (smallpox vaccinia) Vaccine, the only FDA-approved (2007)vaccine for active immunization against smallpox for those at a medical high risk of contracting the disease, from Sanofi Pasteur. Two years later, the Office of the Assistant Secretary for Preparedness and Response , Department of Health and Human Services, has signed a contract with the company worth an estimated US$2.8 billion for the company to provide ACAM2000 over a ten-year period. In 2018, Emergent acquired Adapt Pharma, the manufacturer of Narcan ( naloxone ), a widely used nasal spray opioid-overdose antidote, for $735 million. Adapt is headquartered in Dublin, Ireland, and operates from Radnor, PA. Emergent purchased (also in 2018) the specialty vaccine manufacturer PaxVax, whose product line includes FDA-approved typhoid vaccine Vivotif and cholera vaccine Vaxchora, from its owner, Cerebus Capital Management, a private equity fund. Vaxchora is the only oral vaccine against cholera approved by the FDA in the US. The acquisition also includes rights to vaccines in development. One of these vaccines is being tested as a prophylactic against the acute-respiratory disease adenovirus. Another is focused on the chikungunya virus which is transmitted by mosquitoes. The transaction provides Emergent with a Swiss R&D facility. Fuad El-Hibri (deceased, April 23, 2022), the founder of the company and former CEO, led the company since its founding as BioPort Inc. until his retirement on April 1, 2012. El-Hibri continued to serve as the executive chairman of Emergent BioSolutions' board of directors until shortly before his death in 2022. Robert G. Kramer Sr. became the company's president and CEO April 1, 2019. Prior to that, he was the president and chief operating officer. He has also served as Chief Operating Officer, Chief Financial Officer and other management positions within the corporation. He received his BA from Clemson University and an MBA from Western Kentucky University. In April 2021, the Washington Post reported that Kramer sold $10 million worth of company stock in January and early February 2021 under a November 13, 2020, SEC Rule 10b-5 trading plan, which allows company executives to comply with insider trading laws by setting up predetermined plans to sell company stock. The sale was executed prior to announcements in March about Johnson & Johnson vaccine doses being discarded as well as subsequent ending production of the AstraZeneca vaccine at the Baltimore plant, but the trading plan was set up after the company had experienced COVID-19 vaccine production issues earlier in 2020 . On April 19, 2021, the United States House Select Oversight Subcommittee on the Coronavirus Crisis announced an investigation into Emergent BioSolutions, requesting documents and testimony from El-Hibri and Kramer regarding "federal contracts since 2015, all communication with Kadlec as well as information on audits and inspections of its facilities, drug pricing and executive compensation." Later in April, shareholders filed a class action lawsuit against the company, alleging that they were misled by company executives regarding the company's COVID-19 production capacity. Kramer's previous significant sale of company stock under a SEC Rule 10b-5 plan was in April 2016, and several other Emergent executives also sold stock at that time. The share price subsequently fell, and a lawsuit was filed by investors regarding misrepresentation of the size of the U.S. government's order for anthrax vaccine from the company. Emergent denied the allegations, but paid the investors a $6.5 million settlement. Kramer and El-Hibri testified before the United States House Select Oversight Subcommittee on the Coronavirus Crisis on May 19, 2021. Kramer acknowledged unsanitary conditions, including mold and peeling paint, at the Baltimore plant. He further initially testified that contamination of the Johnson & Johnson doses "was identified through our quality control procedures and checks and balances." But under questioning, he acknowledged that a Johnson & Johnson lab in the Netherlands, not Emergent, had discovered the contaminated doses. Executive compensation documents made public by the House subcommittee show that the company's board praised El-Hibri, who cashed in stock shares and options worth more than $42 million in 2020. In June 2023, Kramer announced his retirement, effective immediately and was replaced as CEO on an interim basis by Haywood Miller. Emergent BioSolutions is the manufacturer of the controversial BioThrax vaccine. According to the U.S. National Library of Medicine , BioThrax was first made available in 1970. BioThrax (Anthrax Vaccine Adsorbed) , a vaccine licensed by the U.S. Food and Drug Administration . Following a study by scientists from the Centers for Disease Control and Prevention , on December 19, 2008, Emergent received final FDA licensing for use of BioThrax five doses for intramuscular injection. Later in 2009, Emergent received approval from the FDA to extend the shelf life of its anthrax vaccine from three to four years. BioThrax was approved for distribution in the United States in the US in 2015. BioThrax has received marketing approval in India, Singapore, and Germany. Health Canada , under the agency's Extraordinary Use New Drug Regulations, approved BioThrax for exclusive use against anthrax for an eight-year period. The Regulations provide a dual track for products allowing human usage while gathering clinical data on the effects of that usage. Additionally, the company has applied for approval of BioThrax in France, Poland, United Kingdom, Italy and the Netherlands. The FDA gave BioThrax an "orphan drug" designation in April 2014. The FDA gives that status to drugs that are used to treat rare diseases. BioThrax is the only anthrax vaccine licensed by the FDA. Another company, VaxGen had received an $877.5 million contract to produce an alternative anthrax vaccine that was reported to "cause fewer side effects", require fewer injections, and have faster effectiveness. Following lobbying from Emergent BioSolutions, VaxGen's contract was cancelled in 2006 due to "poor performance", and development of their anthrax vaccine stopped. As of April 2014, Emergent has sold over 66 million doses of BioThrax to the U.S. government. Three million U.S. military personnel have received the BioThrax vaccine. The main buyer of BioThrax is the U.S. Centers for Disease Control and Prevention (CDC). The CDC buys BioThrax for the Strategic National Stockpile (SNS). The government uses the SNS to protect the public in the event of a national emergency like a terrorist attack. As of December 2016, Emergent has a $911 million contract with the CDC for BioThrax. The BioThrax vaccines will go to the SNS. The contract will supply around 29.4 million doses of the vaccine. Additionally, the Biomedical Advanced Research and Development Authority (BARDA) released a notice of intent to purchase around $100 million of BioThrax for the SNS in 2017. Emergent submitted an application to the FDA for use of a large facility in Lansing, Michigan to produce BioThrax. On June 21, 2016, Emergent announced that it had moved a step forward in the process: the FDA completed the pre-approval phase of its inspection. A company facilities in Canton, Massachusetts was cited by the FDA in 2017 for failing to eliminate low levels of mold and yeast detected in the plant. The vaccine-vial filling Camden facility in Baltimore was cited for failure to conduct routine audits in 2018. In April, 2020, the FDA cited the Bayview facility in Baltimore for insufficient employee training, lack of electronic data security, and failure to investigate "data integrity concerns". The New York Times reported in March 2021 that the US government had spent nearly a quarter of a billion dollars annually, nearly half of its budget to maintain the Strategic National Stockpile, to purchase BioThrax from Emergent during the preceding decade. In 2020, the government paid Emergent US$626 million. The report indicated that these purchases depleted funds needed to purchase vaccines and other supplies to respond to COVID-19 or other pandemics, despite prior warnings about the spending. The early 21st century set in motion the US opioid epidemic , "the most serious and most important public health crisis today", according to the Mayo Clinic Proceedings. Nasal spray naloxone, trade name "Narcan", use has increased markedly during the opioid emergency. The epidemic is measured in overdose deaths, and also is seen in a downturn in overall health and the population's sense of well-being. Increased employment of naloxone such as Narcan among first responders and the public as a whole has reduced mortality, but recidivism is high. The US Opioid Epidemic has intensified the need for and continued use of Narcan to save those suffering from overdoses. The number of opioid deaths in the US doubled from 2010 to 2016 to 42,249 according to the FDA. Narcan is mostly used as a "rescue drug" for individuals suffering from opioid overdose. Narcan, related to morphine, is an opioid antagonist that was originally synthesized and patented by Mozes J. Lewenstein and Jack Fishman in the US in 1961. The drug was patented in the UK by the Japanese company Sankyo (now Daiichi Sankyo ). The US FDA approved the drug in treatment of opioid overdose in 1971. In 2012, concerned about inconsistency of dosage, along with the need for a responder having some specialized training in making the naloxone injection in a tense, highly- charged emergency environment, Phil Skolnick , then director of the Division of Therapeutics & Medical Consequences at the National Institute on Drug Abuse and Roger Crystal, the chief executive officer of Lightlake Therapeutics (now Opiant Pharmaceuticals), teamed to develop an intranasal version of the drug. NIDA then generated a highly concentrated solution of naloxone which Lightlake was able to package in its nasal spray devices. After successful clinical trials, Lightlake entered into a partnership with Adapt Pharma to manufacture the product, Narcan. The FDA approved Narcan nasal spray in November, 2015. Emergent Biosolutions purchased Adapt Pharma in 2018. In January 2019, the FDA initiated a policy that allows the distribution of naloxone over-the-counter through the use of consumer-friendly labels that Emergent Biosolutions uses in delivering Narcan to consumers. Emergent is required by the FDA to make certain that the product-specific parts of the labels are understood by consumers. By 2019, seven states - California, Virginia, Arizona, Ohio, Washington, Vermont and Rhode Island – required physicians to provide patients who receive opioid prescriptions (e.g., as a pain killer) to co-prescribe or, at minimum, offer Narcan to high risk patients. Many doctors consider this practice an opportunity to initiate a discussion between health care providers and patients about the dangers and risks of opioid pain medication. Throughout the US, Narcan and naloxone have been made available OTC in 41 states; exceptions are Delaware, Hawaii, Kansas, Maine, Michigan, Nebraska, Oklahoma, South Dakota and Wyoming. The drug can be found in major retailers like CVS, Walgreens, Walmart and Kroger, as well as independent pharmacies. Many states offer lists of retailers where Narcan can be purchased. Narcan is covered by many health insurance plans. In 2020, the company signed a $135 million deal with Johnson & Johnson to provide and reserve manufacturing capacity for J&J's COVID-19 vaccine candidate for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus which causes COVID-19 . Human testing began later that year, and the vaccine received Emergency Use Authorization from the FDA in February 2021. In June 2020, Cambridge UK-based pharmaceutical developer and manufacturer, AstraZeneca , initiated a $174 million agreement with the company to help develop and produce 300 million doses of the Oxford–AstraZeneca COVID-19 vaccine . AstraZeneca had also signed a previous agreement with Emergent for $87 million (US) naming Emergent a development partner for the vaccine, which was manufactured at the company's Bayview plant in East Baltimore, Maryland. Emergent's manufacturing facility in East Baltimore had previously received $163 million from the US government to make upgrades in order to increase production of vaccines and therapies, including the Johnson & Johnson and AstraZeneca COVID-19 vaccines. However, the plant experienced multiple production issues, and audits in 2020 from several institutions, including internal audits from Emergent, as well as external ones from AstraZeneca, Johnson & Johnson, and U.S. federal government agencies identified issues with deficiencies in employee training, cross-contamination, improper disinfection, and inadequate testing of raw materials. Due to issues with contamination or suspected contamination at the plant between October 2020 and January 2021, 2-3 million doses of AstraZeneca vaccine had to be thrown out, and improper manufacturing of cells in November 2020 caused a batch of Johnson & Johnson vaccine to be thrown out. Later, in March 2021, workers at the Baltimore plant conflated the ingredients of two COVID-19 vaccines, ruining about 15 million doses of Johnson & Johnson's vaccine, and causing them to be discarded. The mix-up, which federal officials attributed to human error, delayed future shipments of the vaccine. The New York Times reported on April 5, 2021, that: "Emergent BioSolutions has made about 150 million doses of Covid-19 vaccines at its Baltimore factory. But so far not a single dose has been usable." As of April 2021, 62 million doses of the Johnson & Johnson vaccine produced at the plant were not discarded but have yet to be distributed, pending assessment for contamination. Consequently, in April 2021, the U.S. Department of Health and Human Services ordered that the plant cease manufacturing of the AstraZeneca vaccine, and that a leadership team from Johnson & Johnson be put in place to run production and manufacturing at the plant, although the workers there are still from Emergent. Amid these issues, the U.S. government announced an additional $23 million in funding for the plant for increased production of the Johnson & Johnson vaccine on April 5, 2021, but because the Astra-Zeneca vaccine was not under production, the Biden administration was no longer paying fees to Emergent tied to the production of that vaccine. Subsequently, on April 17, Emergent announced that the plant had shut down all vaccine production following a request and further investigation from the FDA; as of June 2021, the plant has not re-opened. By June, a combined 75 million vaccine doses were condemned, with approximately 90 million vaccine doses remaining in storage pending further FDA decisions. The FDA cleared a total of 25 million vaccine doses for domestic and international distribution, but with a warning to recipients that "regulators cannot guarantee that Emergent BioSolutions ... followed good manufacturing practices ." In July 2021 the US Food and Drug Administration (FDA) authorized the company's Baltimore plant to restart the manufacturing of J&J Janssen one-dose vaccines, based upon "current observations of the implemented corrective actions". When the plant returns to full capacity in the fall, it can produce up to 120 million doses per month. The company, working with J&J, will persevere in getting FDA approval for doses manufactured at the facility earlier. The US government is looking for doses for export to countries seeking COVID-19 immunization. As of August 2021, the US Food and Drug Administration (FDA) authorized eight batches of Johnson & Johnson's COVID-19 vaccine produced at the Emergent BioSolutions Bayview facility. Starting in March 2021, millions of doses of the AstraZeneca vaccine produced at the Baltimore plant, which were in storage and awaiting approval for use in the U.S., were loaned to Canada and Mexico, where that vaccine had been approved for emergency use. At the time the vaccines were loaned, the U.S. government was reportedly unaware at the time of prior production issues at the plant prior to reporting from the New York Times . AstraZeneca stated that the vaccines distributed had met all "required safety tests and quality control measures"; Canadian and Mexican officials stated that they had reviewed quality and safety documentation provided by the company and that the vaccines were safe for use. In late April 2021, 300,000 doses of the Johnson & Johnson vaccine were sent to Canada. Health Canada delayed the distribution of the vaccine because a substance used in the J&J vaccines was produced at Emergent BioSolutions' Baltimore facility. It was announced in June that Canada would not distribute these doses. Similarly, millions of doses of the Johnson and Johnson vaccine produced at the Baltimore plant were distributed to countries in the European Union and South Africa, as well as manufactured vaccine components to South Africa: although doses from one batch were declared safe for administration in the EU, approximately 6-9 million doses were sequestered for further quality testing as of May 2021 due to concerns regarding contamination. The company also initially teamed with Novavax Inc., a bio-technology company also based in Gaithersburg, MD., in the development and manufacture of the Novavax COVID-19 vaccine . Emergent petitioned the federal government's Biomedical Advanced Research and Development Authority ( BARDA ) to be chosen for the project, and was selected to produce the vaccine in one of its Maryland facilities. However, following production issues with the Johnson & Johnson and Oxford–AstraZeneca vaccines at its Baltimore plant and to decrease the burden on the plant, Novavax subsequently partnered with a different manufacturer in a new agreement overseen by the U.S. government. In 2020, the company signed a $135 million deal with Johnson & Johnson to provide and reserve manufacturing capacity for J&J's COVID-19 vaccine candidate for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus which causes COVID-19 . Human testing began later that year, and the vaccine received Emergency Use Authorization from the FDA in February 2021. In June 2020, Cambridge UK-based pharmaceutical developer and manufacturer, AstraZeneca , initiated a $174 million agreement with the company to help develop and produce 300 million doses of the Oxford–AstraZeneca COVID-19 vaccine . AstraZeneca had also signed a previous agreement with Emergent for $87 million (US) naming Emergent a development partner for the vaccine, which was manufactured at the company's Bayview plant in East Baltimore, Maryland. Emergent's manufacturing facility in East Baltimore had previously received $163 million from the US government to make upgrades in order to increase production of vaccines and therapies, including the Johnson & Johnson and AstraZeneca COVID-19 vaccines. However, the plant experienced multiple production issues, and audits in 2020 from several institutions, including internal audits from Emergent, as well as external ones from AstraZeneca, Johnson & Johnson, and U.S. federal government agencies identified issues with deficiencies in employee training, cross-contamination, improper disinfection, and inadequate testing of raw materials. Due to issues with contamination or suspected contamination at the plant between October 2020 and January 2021, 2-3 million doses of AstraZeneca vaccine had to be thrown out, and improper manufacturing of cells in November 2020 caused a batch of Johnson & Johnson vaccine to be thrown out. Later, in March 2021, workers at the Baltimore plant conflated the ingredients of two COVID-19 vaccines, ruining about 15 million doses of Johnson & Johnson's vaccine, and causing them to be discarded. The mix-up, which federal officials attributed to human error, delayed future shipments of the vaccine. The New York Times reported on April 5, 2021, that: "Emergent BioSolutions has made about 150 million doses of Covid-19 vaccines at its Baltimore factory. But so far not a single dose has been usable." As of April 2021, 62 million doses of the Johnson & Johnson vaccine produced at the plant were not discarded but have yet to be distributed, pending assessment for contamination. Consequently, in April 2021, the U.S. Department of Health and Human Services ordered that the plant cease manufacturing of the AstraZeneca vaccine, and that a leadership team from Johnson & Johnson be put in place to run production and manufacturing at the plant, although the workers there are still from Emergent. Amid these issues, the U.S. government announced an additional $23 million in funding for the plant for increased production of the Johnson & Johnson vaccine on April 5, 2021, but because the Astra-Zeneca vaccine was not under production, the Biden administration was no longer paying fees to Emergent tied to the production of that vaccine. Subsequently, on April 17, Emergent announced that the plant had shut down all vaccine production following a request and further investigation from the FDA; as of June 2021, the plant has not re-opened. By June, a combined 75 million vaccine doses were condemned, with approximately 90 million vaccine doses remaining in storage pending further FDA decisions. The FDA cleared a total of 25 million vaccine doses for domestic and international distribution, but with a warning to recipients that "regulators cannot guarantee that Emergent BioSolutions ... followed good manufacturing practices ." In July 2021 the US Food and Drug Administration (FDA) authorized the company's Baltimore plant to restart the manufacturing of J&J Janssen one-dose vaccines, based upon "current observations of the implemented corrective actions". When the plant returns to full capacity in the fall, it can produce up to 120 million doses per month. The company, working with J&J, will persevere in getting FDA approval for doses manufactured at the facility earlier. The US government is looking for doses for export to countries seeking COVID-19 immunization. As of August 2021, the US Food and Drug Administration (FDA) authorized eight batches of Johnson & Johnson's COVID-19 vaccine produced at the Emergent BioSolutions Bayview facility. Starting in March 2021, millions of doses of the AstraZeneca vaccine produced at the Baltimore plant, which were in storage and awaiting approval for use in the U.S., were loaned to Canada and Mexico, where that vaccine had been approved for emergency use. At the time the vaccines were loaned, the U.S. government was reportedly unaware at the time of prior production issues at the plant prior to reporting from the New York Times . AstraZeneca stated that the vaccines distributed had met all "required safety tests and quality control measures"; Canadian and Mexican officials stated that they had reviewed quality and safety documentation provided by the company and that the vaccines were safe for use. In late April 2021, 300,000 doses of the Johnson & Johnson vaccine were sent to Canada. Health Canada delayed the distribution of the vaccine because a substance used in the J&J vaccines was produced at Emergent BioSolutions' Baltimore facility. It was announced in June that Canada would not distribute these doses. Similarly, millions of doses of the Johnson and Johnson vaccine produced at the Baltimore plant were distributed to countries in the European Union and South Africa, as well as manufactured vaccine components to South Africa: although doses from one batch were declared safe for administration in the EU, approximately 6-9 million doses were sequestered for further quality testing as of May 2021 due to concerns regarding contamination. The company also initially teamed with Novavax Inc., a bio-technology company also based in Gaithersburg, MD., in the development and manufacture of the Novavax COVID-19 vaccine . Emergent petitioned the federal government's Biomedical Advanced Research and Development Authority ( BARDA ) to be chosen for the project, and was selected to produce the vaccine in one of its Maryland facilities. However, following production issues with the Johnson & Johnson and Oxford–AstraZeneca vaccines at its Baltimore plant and to decrease the burden on the plant, Novavax subsequently partnered with a different manufacturer in a new agreement overseen by the U.S. government. The company has been developing a vaccine to counter chikungunya , a mosquito-borne virus that was mostly found, until the past decade, only in central and East Africa. Then it began growing. E.g., in 2011, there were zero cases reported in Latin America; in 2014 the region suffered from one million cases. Between 2010 and 2019 the virus is estimated to have been responsible for 106,000 average annual disability-adjusted life years (DALY). In 2018 the FDA conferred its "Fast Track" designation on the company's investigational chikungunya virus virus-like particle (CHIKV VLP) vaccine candidate. The following year, 2019, the European Medicines Agency awarded its PRIME (Priority Medicines) designation to CHIKV VLP as well. Companies who receive the PRIME nod can get magnified interchanges and timely interaction with EMA to accelerate development and approval. The CHIKV VLP vaccine candidate is licensed by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. In May 2021, the company reported that its single-dose vaccine demonstrated strong efficacy two years after injection, with an increase in immune response when measured by serum neutralizing antibodies (SNA). One of Emergent's medical countermeasure products is Reactive Skin Decontamination Lotion (RSDL), a lotion that clears and neutralizes chemical warfare agents. The product, used internationally, was tested in a study conducted by the US Army Medical Research Institute of Chemical Defense, where RSDL was found to provide superior protection against soman when decontamination was commenced within three minutes of exposure. RSDL is made of the chemicals Dekon 139 2,3 butanedione monoxime (DAM). According to the Chemical Hazards Emergency Medical Management office within the United States Department of Health and Human Services, "RSDL is used as a medical device for the decontamination of skin exposed to chemical warfare agents such as sulfur mustard, VX, VR and certain biological toxins." As of September 2017, RSDL is available to the regular public. Previously, it was only available to the military. The United States Department of Defense in September 2017 awarded the company a contract to supply the RSDL kit (RSDL) to the military. The contract is for five years and is worth $171 million. The RSDL lotion protects people's skin from various chemical warfare agents. The product contains a sponge that is filled with the decontamination lotion in and impermeable packet. When applied to the skin, the lotion reacts with the agent on the skin and quickly neutralizes it so that it becomes non-toxic. The Medical CBRN (Chemical, Biological, Radiological and Nuclear) Defense Consortium, a DOD initiative within its Joint Program Executive Office for Chemical and Biological Defense has awarded the company US$20 million to develop an auto-injector to administer diazepam. The injection is designed to reverse the effects of nerve agents in military or chemical terrorism situations. The investment supports R&D, manufacturing and negotiating the approval process with the US FDA. The company joined forces with New York City's Mount Sinai Health System and ImmunoTek Bio Centers (New Orleans LA) to research, develop, conduct clinical trials, and manufacture COVID-HIG, hyperimmune globulin, also known as polyclonal antibodies, a concentrated antibody made from plasma acquired from individuals infected with and recovered from COVID-19. The research is designed to determine whether COVID-HIG could protect people at higher risk of exposure and infection (like health care and military personnel) and therefore limit the spread of the infection. The initial study is funded by a $34.6 million (US) grant from the US Dept. of Defense and the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND). The company has been developing a vaccine to counter chikungunya , a mosquito-borne virus that was mostly found, until the past decade, only in central and East Africa. Then it began growing. E.g., in 2011, there were zero cases reported in Latin America; in 2014 the region suffered from one million cases. Between 2010 and 2019 the virus is estimated to have been responsible for 106,000 average annual disability-adjusted life years (DALY). In 2018 the FDA conferred its "Fast Track" designation on the company's investigational chikungunya virus virus-like particle (CHIKV VLP) vaccine candidate. The following year, 2019, the European Medicines Agency awarded its PRIME (Priority Medicines) designation to CHIKV VLP as well. Companies who receive the PRIME nod can get magnified interchanges and timely interaction with EMA to accelerate development and approval. The CHIKV VLP vaccine candidate is licensed by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. In May 2021, the company reported that its single-dose vaccine demonstrated strong efficacy two years after injection, with an increase in immune response when measured by serum neutralizing antibodies (SNA). One of Emergent's medical countermeasure products is Reactive Skin Decontamination Lotion (RSDL), a lotion that clears and neutralizes chemical warfare agents. The product, used internationally, was tested in a study conducted by the US Army Medical Research Institute of Chemical Defense, where RSDL was found to provide superior protection against soman when decontamination was commenced within three minutes of exposure. RSDL is made of the chemicals Dekon 139 2,3 butanedione monoxime (DAM). According to the Chemical Hazards Emergency Medical Management office within the United States Department of Health and Human Services, "RSDL is used as a medical device for the decontamination of skin exposed to chemical warfare agents such as sulfur mustard, VX, VR and certain biological toxins." As of September 2017, RSDL is available to the regular public. Previously, it was only available to the military. The United States Department of Defense in September 2017 awarded the company a contract to supply the RSDL kit (RSDL) to the military. The contract is for five years and is worth $171 million. The RSDL lotion protects people's skin from various chemical warfare agents. The product contains a sponge that is filled with the decontamination lotion in and impermeable packet. When applied to the skin, the lotion reacts with the agent on the skin and quickly neutralizes it so that it becomes non-toxic. The Medical CBRN (Chemical, Biological, Radiological and Nuclear) Defense Consortium, a DOD initiative within its Joint Program Executive Office for Chemical and Biological Defense has awarded the company US$20 million to develop an auto-injector to administer diazepam. The injection is designed to reverse the effects of nerve agents in military or chemical terrorism situations. The investment supports R&D, manufacturing and negotiating the approval process with the US FDA. The company joined forces with New York City's Mount Sinai Health System and ImmunoTek Bio Centers (New Orleans LA) to research, develop, conduct clinical trials, and manufacture COVID-HIG, hyperimmune globulin, also known as polyclonal antibodies, a concentrated antibody made from plasma acquired from individuals infected with and recovered from COVID-19. The research is designed to determine whether COVID-HIG could protect people at higher risk of exposure and infection (like health care and military personnel) and therefore limit the spread of the infection. The initial study is funded by a $34.6 million (US) grant from the US Dept. of Defense and the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND). In October 2018, the company donated two doses of Narcan nasal spray to all 16,568 libraries in the US. Emergent had previously donated 20,000 doses to 4,700 universities in the US in 2017. It later expanded this donation to all US high schools as well. Additionally, the company donated free Narcan kits to 2,700 YMCAs across the US. Narcan and naloxone are offered at major drug retailers like Walgreens and CVS in many states without a prescription. The obstacles created by the worldwide COVID-19 pandemic resulted in over 90,000 opioid overdose fatalities in 2020, reflecting the global crisis' effect on attempts to stop the increase of the synthetic opioid fentanyl in the illegal narcotics supply, according to the US Centers for Disease Control (CDC). With the focus of healthcare resources extended to quell the coronavirus emergency, more substance abuse users found it difficult to obtain treatment and medication. They were also more isolated, restricting outreach to first responders and access to naloxone (Narcan). The US government has made resisting the opioid crisis an "urgent priority". In July 2021, Emergent Biosolutions teamed with a group of individuals and organizations by sponsoring a program to focus attention on the current opioid overdose emergency. The campaign, called Reverse the Silence , provides an unbranded website and national television and radio commercials focused on diminishing the ignominy of opioid addiction and overdose. Program participants include former Congresswoman Mary Bono , NFL star Darren Waller and four addiction advocacy groups. The campaign urges substance use abusers, their families, friends and others to "speak up" for people living with addiction. The campaign's website is not tied to Narcan specifically but offers a plethora of naloxone resources and information on how the drug works and where to obtain it. The site mentions that every state allows individuals to obtain naloxone without a prescription. Emergent Biosolutions was among many companies giving financial support to delegations at both major party political conventions in the summer of 2016, a practice that "watchdog groups have raised concerns about ... as corporate donors — skittish about Republican nominee Donald J. Trump — have sought new and less overt ways to give money and gain influence". Emergent Biosolutions PAC donated tens of thousands of dollars in 2020 to both Republicans and Democrats from Joe Biden and Dick Durbin to Andy Harris and Mitch McConnell. The majority of contributions were directed to Democrats (37.6%), but the amount donated favored Republicans (62.4%). In October 2018, the company donated two doses of Narcan nasal spray to all 16,568 libraries in the US. Emergent had previously donated 20,000 doses to 4,700 universities in the US in 2017. It later expanded this donation to all US high schools as well. Additionally, the company donated free Narcan kits to 2,700 YMCAs across the US. Narcan and naloxone are offered at major drug retailers like Walgreens and CVS in many states without a prescription. The obstacles created by the worldwide COVID-19 pandemic resulted in over 90,000 opioid overdose fatalities in 2020, reflecting the global crisis' effect on attempts to stop the increase of the synthetic opioid fentanyl in the illegal narcotics supply, according to the US Centers for Disease Control (CDC). With the focus of healthcare resources extended to quell the coronavirus emergency, more substance abuse users found it difficult to obtain treatment and medication. They were also more isolated, restricting outreach to first responders and access to naloxone (Narcan). The US government has made resisting the opioid crisis an "urgent priority". In July 2021, Emergent Biosolutions teamed with a group of individuals and organizations by sponsoring a program to focus attention on the current opioid overdose emergency. The campaign, called Reverse the Silence , provides an unbranded website and national television and radio commercials focused on diminishing the ignominy of opioid addiction and overdose. Program participants include former Congresswoman Mary Bono , NFL star Darren Waller and four addiction advocacy groups. The campaign urges substance use abusers, their families, friends and others to "speak up" for people living with addiction. The campaign's website is not tied to Narcan specifically but offers a plethora of naloxone resources and information on how the drug works and where to obtain it. The site mentions that every state allows individuals to obtain naloxone without a prescription. Emergent Biosolutions was among many companies giving financial support to delegations at both major party political conventions in the summer of 2016, a practice that "watchdog groups have raised concerns about ... as corporate donors — skittish about Republican nominee Donald J. Trump — have sought new and less overt ways to give money and gain influence". Emergent Biosolutions PAC donated tens of thousands of dollars in 2020 to both Republicans and Democrats from Joe Biden and Dick Durbin to Andy Harris and Mitch McConnell. The majority of contributions were directed to Democrats (37.6%), but the amount donated favored Republicans (62.4%).

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Chikungunya

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Coalition for Epidemic Preparedness Innovations

The Coalition for Epidemic Preparedness Innovations ( CEPI ) is a foundation that takes donations from public, private, philanthropic, and civil society organisations, to finance independent research projects to develop vaccines against emerging infectious diseases (EID). CEPI is focused on the World Health Organization 's (WHO) " blueprint priority diseases ", which include: the Middle East respiratory syndrome-related coronavirus ( MERS-CoV ), the Severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ), the Nipah virus , the Lassa fever virus , and the Rift Valley fever virus, as well as the Chikungunya virus and the hypothetical, unknown pathogen " Disease X ". CEPI investment also requires "equitable access" to the vaccines during outbreaks , although subsequent CEPI policy changes may have compromised this criterion. In 2022, CEPI adopted a vision for the world to be able to respond to a pandemic threat with a new vaccine within 100 days. CEPI was conceived in 2015 and formally launched in 2017 at the World Economic Forum (WEF) in Davos , Switzerland. It was co-founded and co-funded with US$460 million from the Bill and Melinda Gates Foundation , the Wellcome Trust , and the governments of India and Norway , and was later joined by the European Union (2019) and the United Kingdom (2020). CEPI is headquartered in Oslo , Norway. The concept for CEPI was outlined in a July 2015 paper in The New England Journal of Medicine , titled "Establishing a Global Vaccine-Development Fund", co-authored by British medical researcher Jeremy Farrar (a director of Wellcome Trust ), American physician Stanley A. Plotkin (co-discoverer of the Rubella vaccine), and American expert in infectious diseases Adel Mahmoud (developer of the HPV vaccine and rotavirus vaccine ). Their concept was further expanded at the 2016 WEF in Davos, where it was discussed as a solution to the problems encountered in developing and distributing a vaccine for the Western African Ebola virus epidemic . Co-founder and funder, Bill Gates said: "The market is not going to solve this problem because epidemics do not come along very often — and when they do you are not allowed to charge some huge premium price for the tools involved". CEPI's creation was also supported and co-funded by the pharmaceutical industry including GlaxoSmithKline (GSK), with CEO Sir Andrew Witty explaining at the WEF, "It is super-disruptive when the red phone rings in our vaccine division because of a health emergency. People do not realise that there's no spare capacity in the world's vaccine production system today". CEPI was formally launched at the 2017 WEF in Davos, with an initial investment of US$460 million by a consortium that included the governments of Norway, Japan, and Germany, The Wellcome Trust, and the Gates Foundation ; India joined a short time afterwards. In a launch interview with the Financial Times (FT), Gates said that a key goal was to reduce the time to develop vaccines from 10 years to less than 12 months. The initial targets were the six EID viruses with known potential to cause major epidemics, being: MERS , Lassa fever , Nipah virus , Ebola , Marburg fever and Zika . The FT reported CEPI would "build the scientific and technological infrastructure for developing vaccines quickly against pathogens that emerge from nowhere to cause a global health crisis, such as Sars in 2002/03 and Zika in 2015/16", and fund research papers on the costs and process of vaccine development. Town & Country listed it as one of the top-10 newsworthy moments from the 2017 Davos. At launch, Norwegian physician John-Arne Røttingen , who led the steering committee for Ebola vaccine trials, served as interim CEO, and CEPI was based at the Norwegian Institute of Public Health in Oslo. In April 2017, Richard J. Hatchett, former director of the U.S. government's Biomedical Advanced Research and Development Authority (BARDA), became the full-time CEO. Hatchett was also a member of the United States Homeland Security Council under George W. Bush , and the United States National Security Council , under Barack Obama . Also in April 2017, CEPI opened an additional office in London, and in October 2017, a further office was opened in Washington, D.C. Nature later stated, "It is by far the largest vaccine development initiative ever against viruses that are potential epidemic threats". In 2020, CEPI was identified by several media outlets as a "key player in the race to develop a vaccine" for coronavirus disease 2019 . At its launch in 2017, CEPI announced five-year financial pledges from its founders that amounted to US$460 million and came from the sovereign governments of Japan (US$125 million), Norway (US$120 million), and Germany (US$10.6 million in 2017 alone, and which later became US$90 million), and from global foundations of the Gates Foundation (US$100 million), and the Wellcome Trust (US$100 million); India was finalising their financial commitment, which was made shortly afterward. A funding target of US$1 billion was set for the first 5 years of operation (i.e. by January 2022). The journal Nature said of the amount raised that: "It is by far the largest vaccine development initiative ever against viruses that are potential epidemic threats". As part of its funding structure, CEPI has used "vaccine bonds" to "frontload" multi-year sovereign funding pledges. In 2019, the International Finance Facility for Immunisation (IFFIm) issued NOK 600 million in vaccine bonds to front-load the commitment by Norway, through Gavi, the Vaccine Alliance , to CEPI. In March 2019, the European Commission granted access to CEPI into the EU's Horizon 2020 programme, and a longer-term financial funding programme. CEPI note presentations that the EU's financial commitment amounts to US$200 million, which when added to the seed amount (including the full German commitment), came to US$740 million. By February 2020, Bloomberg News reported that CEPI had raised a total of US$760 million with additional donations from the governments of Australia, Belgium, Canada, and the U.K. Bloomberg said that "CEPI solves what economists call a 'coordination problem'. It can help pair boutique research and development companies with big vaccine manufacturers, work with regulators to streamline approval processes and resolve patent disputes on the spot. Its scientific advisory committee has executives from Pfizer, Johnson & Johnson, and Japan's Takeda Pharmaceutical, among others". In March 2020, the British government pledged £210 million in funding to CEPI to specifically focus on a vaccine for the coronavirus; making Britain CEPI's largest individual donor. In January 2022, The Wellcome Trust and the Bill & Melinda Gates Foundation pledged $300 million to CEPI. This is part of CEPI's effort to enable the world to reduce vaccine development timelines to 100 days. The founding mission of CEPI was "equitable access" in pandemics: selling vaccines to developing nations at affordable prices. Affordable access to existing patented vaccines had long been a concern for the medical community, and concern mounted in the wake of the struggle to get access to vaccine in the 2013–2016 Ebola epidemic . Averting a repetition of this crisis was the motivating factor behind founding CEPI. CEPI's original policy contained specific measures to prevent some of these market problems. All vaccine-manufacturing contracts would need initial approval by a public review board. The policy also stated that vaccine prices would be set at levels affordable to those needing vaccines and sustainable to the manufacturer. Trade secrets would not be funded by the CEPI. Companies had to share all research data developed with CEPI funds. While CEPI would, controversially, not retain and license the intellectual property developed with CEPI funds (allowing the groups awarded funding to own it), the CEPI retained "step-in" rights: the right to license and use intellectual property developed with CEPI funds for vaccine production, even if the company that had received the funding and taken ownership of the IP later withdrew from the agreement with CEPI. The original policy also required that funded parties pre-register any trials in a clinical trials registry , publish results within a year of study completion (except with compelling reason and permission of CEPI), publish results in open-access articles, and have mechanisms for securely sharing underlying data and results, including negative results, in a way that preserves trial volunteer privacy (see AllTrials for further information). Pharmaceutical corporations, including Johnson & Johnson , Pfizer , and Takeda , objected to the original policy, and these provisions were removed in December 2018, after the CEPI had obtained significant funding. The policy changes met with strong criticism, led by Médecins Sans Frontières . CEPI was also criticized for not following its own policies on transparency, and for removing the requirement that CEPI's board review CEPI's contracts. The CEPI stated that its vaccines would continue to be affordable and available, and published an article discussing the changes, saying that the old policy "while reflective of the idealism that inspired the creation of CEPI, was felt by others not to be pragmatic or reflect the business realities confronted by vaccine developers". It said that several unnamed vaccine manufacturers had declared that they could not work with the CEPI under the original policy. It said that the policy change did not reflect a change in commitment to access, and CEPI would still retain the right to do research and development using intellectual property it had funded, if the old partner was unable to continue. It also said that the CEPI would retain the right to find a new manufacturer if the old manufacturer could not continue, provided the old manufacturer agrees to the transfer of the information and intellectual property to the new one. The New York Times said that CEPI had made a "failed effort to get large pharmaceutical firms to agree to be partners without insisting on substantial profits or proprietary rights to research that CEPI helped to finance and produce," and had replaced specific implementation measures with lip service to its funding mission. The coalition was nominated for the 2021 Nobel Peace Prize by Norwegian MP Carl-Erik Grimstad . The concept for CEPI was outlined in a July 2015 paper in The New England Journal of Medicine , titled "Establishing a Global Vaccine-Development Fund", co-authored by British medical researcher Jeremy Farrar (a director of Wellcome Trust ), American physician Stanley A. Plotkin (co-discoverer of the Rubella vaccine), and American expert in infectious diseases Adel Mahmoud (developer of the HPV vaccine and rotavirus vaccine ). Their concept was further expanded at the 2016 WEF in Davos, where it was discussed as a solution to the problems encountered in developing and distributing a vaccine for the Western African Ebola virus epidemic . Co-founder and funder, Bill Gates said: "The market is not going to solve this problem because epidemics do not come along very often — and when they do you are not allowed to charge some huge premium price for the tools involved". CEPI's creation was also supported and co-funded by the pharmaceutical industry including GlaxoSmithKline (GSK), with CEO Sir Andrew Witty explaining at the WEF, "It is super-disruptive when the red phone rings in our vaccine division because of a health emergency. People do not realise that there's no spare capacity in the world's vaccine production system today". CEPI was formally launched at the 2017 WEF in Davos, with an initial investment of US$460 million by a consortium that included the governments of Norway, Japan, and Germany, The Wellcome Trust, and the Gates Foundation ; India joined a short time afterwards. In a launch interview with the Financial Times (FT), Gates said that a key goal was to reduce the time to develop vaccines from 10 years to less than 12 months. The initial targets were the six EID viruses with known potential to cause major epidemics, being: MERS , Lassa fever , Nipah virus , Ebola , Marburg fever and Zika . The FT reported CEPI would "build the scientific and technological infrastructure for developing vaccines quickly against pathogens that emerge from nowhere to cause a global health crisis, such as Sars in 2002/03 and Zika in 2015/16", and fund research papers on the costs and process of vaccine development. Town & Country listed it as one of the top-10 newsworthy moments from the 2017 Davos. At launch, Norwegian physician John-Arne Røttingen , who led the steering committee for Ebola vaccine trials, served as interim CEO, and CEPI was based at the Norwegian Institute of Public Health in Oslo. In April 2017, Richard J. Hatchett, former director of the U.S. government's Biomedical Advanced Research and Development Authority (BARDA), became the full-time CEO. Hatchett was also a member of the United States Homeland Security Council under George W. Bush , and the United States National Security Council , under Barack Obama . Also in April 2017, CEPI opened an additional office in London, and in October 2017, a further office was opened in Washington, D.C. Nature later stated, "It is by far the largest vaccine development initiative ever against viruses that are potential epidemic threats". In 2020, CEPI was identified by several media outlets as a "key player in the race to develop a vaccine" for coronavirus disease 2019 . At its launch in 2017, CEPI announced five-year financial pledges from its founders that amounted to US$460 million and came from the sovereign governments of Japan (US$125 million), Norway (US$120 million), and Germany (US$10.6 million in 2017 alone, and which later became US$90 million), and from global foundations of the Gates Foundation (US$100 million), and the Wellcome Trust (US$100 million); India was finalising their financial commitment, which was made shortly afterward. A funding target of US$1 billion was set for the first 5 years of operation (i.e. by January 2022). The journal Nature said of the amount raised that: "It is by far the largest vaccine development initiative ever against viruses that are potential epidemic threats". As part of its funding structure, CEPI has used "vaccine bonds" to "frontload" multi-year sovereign funding pledges. In 2019, the International Finance Facility for Immunisation (IFFIm) issued NOK 600 million in vaccine bonds to front-load the commitment by Norway, through Gavi, the Vaccine Alliance , to CEPI. In March 2019, the European Commission granted access to CEPI into the EU's Horizon 2020 programme, and a longer-term financial funding programme. CEPI note presentations that the EU's financial commitment amounts to US$200 million, which when added to the seed amount (including the full German commitment), came to US$740 million. By February 2020, Bloomberg News reported that CEPI had raised a total of US$760 million with additional donations from the governments of Australia, Belgium, Canada, and the U.K. Bloomberg said that "CEPI solves what economists call a 'coordination problem'. It can help pair boutique research and development companies with big vaccine manufacturers, work with regulators to streamline approval processes and resolve patent disputes on the spot. Its scientific advisory committee has executives from Pfizer, Johnson & Johnson, and Japan's Takeda Pharmaceutical, among others". In March 2020, the British government pledged £210 million in funding to CEPI to specifically focus on a vaccine for the coronavirus; making Britain CEPI's largest individual donor. In January 2022, The Wellcome Trust and the Bill & Melinda Gates Foundation pledged $300 million to CEPI. This is part of CEPI's effort to enable the world to reduce vaccine development timelines to 100 days.The founding mission of CEPI was "equitable access" in pandemics: selling vaccines to developing nations at affordable prices. Affordable access to existing patented vaccines had long been a concern for the medical community, and concern mounted in the wake of the struggle to get access to vaccine in the 2013–2016 Ebola epidemic . Averting a repetition of this crisis was the motivating factor behind founding CEPI. CEPI's original policy contained specific measures to prevent some of these market problems. All vaccine-manufacturing contracts would need initial approval by a public review board. The policy also stated that vaccine prices would be set at levels affordable to those needing vaccines and sustainable to the manufacturer. Trade secrets would not be funded by the CEPI. Companies had to share all research data developed with CEPI funds. While CEPI would, controversially, not retain and license the intellectual property developed with CEPI funds (allowing the groups awarded funding to own it), the CEPI retained "step-in" rights: the right to license and use intellectual property developed with CEPI funds for vaccine production, even if the company that had received the funding and taken ownership of the IP later withdrew from the agreement with CEPI. The original policy also required that funded parties pre-register any trials in a clinical trials registry , publish results within a year of study completion (except with compelling reason and permission of CEPI), publish results in open-access articles, and have mechanisms for securely sharing underlying data and results, including negative results, in a way that preserves trial volunteer privacy (see AllTrials for further information). Pharmaceutical corporations, including Johnson & Johnson , Pfizer , and Takeda , objected to the original policy, and these provisions were removed in December 2018, after the CEPI had obtained significant funding. The policy changes met with strong criticism, led by Médecins Sans Frontières . CEPI was also criticized for not following its own policies on transparency, and for removing the requirement that CEPI's board review CEPI's contracts. The CEPI stated that its vaccines would continue to be affordable and available, and published an article discussing the changes, saying that the old policy "while reflective of the idealism that inspired the creation of CEPI, was felt by others not to be pragmatic or reflect the business realities confronted by vaccine developers". It said that several unnamed vaccine manufacturers had declared that they could not work with the CEPI under the original policy. It said that the policy change did not reflect a change in commitment to access, and CEPI would still retain the right to do research and development using intellectual property it had funded, if the old partner was unable to continue. It also said that the CEPI would retain the right to find a new manufacturer if the old manufacturer could not continue, provided the old manufacturer agrees to the transfer of the information and intellectual property to the new one. The New York Times said that CEPI had made a "failed effort to get large pharmaceutical firms to agree to be partners without insisting on substantial profits or proprietary rights to research that CEPI helped to finance and produce," and had replaced specific implementation measures with lip service to its funding mission. CEPI's original policy contained specific measures to prevent some of these market problems. All vaccine-manufacturing contracts would need initial approval by a public review board. The policy also stated that vaccine prices would be set at levels affordable to those needing vaccines and sustainable to the manufacturer. Trade secrets would not be funded by the CEPI. Companies had to share all research data developed with CEPI funds. While CEPI would, controversially, not retain and license the intellectual property developed with CEPI funds (allowing the groups awarded funding to own it), the CEPI retained "step-in" rights: the right to license and use intellectual property developed with CEPI funds for vaccine production, even if the company that had received the funding and taken ownership of the IP later withdrew from the agreement with CEPI. The original policy also required that funded parties pre-register any trials in a clinical trials registry , publish results within a year of study completion (except with compelling reason and permission of CEPI), publish results in open-access articles, and have mechanisms for securely sharing underlying data and results, including negative results, in a way that preserves trial volunteer privacy (see AllTrials for further information). Pharmaceutical corporations, including Johnson & Johnson , Pfizer , and Takeda , objected to the original policy, and these provisions were removed in December 2018, after the CEPI had obtained significant funding. The policy changes met with strong criticism, led by Médecins Sans Frontières . CEPI was also criticized for not following its own policies on transparency, and for removing the requirement that CEPI's board review CEPI's contracts. The CEPI stated that its vaccines would continue to be affordable and available, and published an article discussing the changes, saying that the old policy "while reflective of the idealism that inspired the creation of CEPI, was felt by others not to be pragmatic or reflect the business realities confronted by vaccine developers". It said that several unnamed vaccine manufacturers had declared that they could not work with the CEPI under the original policy. It said that the policy change did not reflect a change in commitment to access, and CEPI would still retain the right to do research and development using intellectual property it had funded, if the old partner was unable to continue. It also said that the CEPI would retain the right to find a new manufacturer if the old manufacturer could not continue, provided the old manufacturer agrees to the transfer of the information and intellectual property to the new one. The New York Times said that CEPI had made a "failed effort to get large pharmaceutical firms to agree to be partners without insisting on substantial profits or proprietary rights to research that CEPI helped to finance and produce," and had replaced specific implementation measures with lip service to its funding mission. The coalition was nominated for the 2021 Nobel Peace Prize by Norwegian MP Carl-Erik Grimstad . CEPI is incorporated under Norwegian law . As of March 2020, a full-time staff of 68 that runs the organisation under the direction of a chief executive officer, Richard Hatchett. In October 2018, CEPI scientists estimated that the costs of developing at least one vaccine for each of the diseases that could escalate into global humanitarian crises was between US$2.8 billion and US$3.7 billion. In November 2019, CEPI discussed its target portfolio was on the WHO 's " blueprint priority diseases ", that included: MERS-CoV, Nipah virus, Lassa fever virus, and Rift Valley fever virus, as well as Chikungunya virus , and the WHO's Disease X . CEPI outlined its projects to update CEPI priorities for establishment of technical and regulatory pathways for vaccine development, develop sustainable manufacturing solutions for vaccine candidates nearing completion, and create investigatory stockpiles of its vaccine candidates for use in emergency situations.

Wiki

Chikungunya

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HLL Lifecare

HLL Lifecare Limited (formerly Hindustan Latex Limited ) ( HLL ) is an Indian healthcare product manufacturing company based in Thiruvananthapuram , Kerala , India . It is a Government of India -owned corporation ( public-sector undertaking ).It produces health care products , including condoms , contraceptive pills , IUDs , surgical sutures , blood bags and Pharma products . One of HLL's contraceptive products is ormeloxifene , branded as Saheli , the world's first and only oral non-hormonal, non-steroidal oral contraceptive , taken as a weekly pill. In 2012, HLL announced a polymerase chain reaction based duplex test kit for chikungunya and dengue fever tests in collaboration with the Rajiv Gandhi Centre for Biotechnology , Trivandrum . In December 2015, they tied up with the Government of India in setting up Amrit pharmacies across India for providing cheaper medicines for Cancer and Cardiovascular disorders. The name Amrit stands for Affordable Medicines and Reliable Implants for Treatment. In 2005, HLL established LifeSpring Hospitals , a 50-50 joint venture with the Acumen Fund , a U.S.-based nonprofit global venture philanthropy fund, to provide low-cost maternity services, starting at Hyderabad . Today it has nine hospitals across Andhra Pradesh state. In February 2014, HLL acquired 74% Equity in Goa Antibiotics and Pharmaceuticals Ltd. HLL has its head office in Thiruvananthapuram and factories in 7 locations across India. Four of the factories were built in Kerala, such as Peroorkada , Aakkulam , Kakkanad and Irapuram . The rest 3 factories are in Belgaum , Manesar , and Indore . HLL currently has 220 pathology labs, 47 imaging centres and 6 labs under the brand name Hindlabs. It runs a total of 253 pharmacies across India. HLL runs a subsidiary with the name of HLL Infra Tech Services Ltd. In 2020-21 the company reported a turnover of ₹5,081 crore. In 2022 due to growing cases of stroke, the cabinet gave permission to have a collaboration with HLL Lifecare to build a hub and spoke model at various primary health centres (PHCs) for the required treatment. On 8 January 2018, the Government of India approved the privatisation of HLL Lifecare. But the Ministry of Health and Family Welfare and the Government of Kerala has opposed the Union Government 's plan for disinvestment of HLL Lifecare Limited. In 2021, the Central Government eventually finalized its plans to divest its whole stake in the company which will make it a private company. The Finance Ministry's Department of Investment and Public Asset Management (DIPAM) on November 14, 2021, revealed a large portion of the company's business comes from central government projects.

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Chikungunya

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Uromune

None Uromune , also known by its developmental code name MV-140 , is a polyvalent bacterial vaccine which is used in the prevention of recurrent urinary tract infections (UTIs). In clinical studies , it has been found to reduce total number of UTIs (by ~70%), to increase UTI-free rates (from 25% to ~57%), and to increase time to next UTI (from 48 days to 275 days), as well as to reduce UTI symptoms, reduce antibiotic use, and improve quality of life , over a period of 9 months following treatment. The effectiveness of the vaccine appears to wane with time, which may necessitate readministration. Uromune is used as a sublingual spray once daily for 3 months. Side effects of Uromune are considered infrequent, minor, and usually not treatment-related. Uromune is an inactivated combination of four major bacteria known to cause recurrent UTIs, including Escherichia coli , Klebsiella pneumoniae , Enterococcus faecalis , and Proteus vulgaris . It is thought to work by increasing adaptive immunity against UTI-causing bacteria and possibly also by increasing trained immunity against these pathogens. Uromune first became available for clinical use in 2010 and was first described in the literature by 2012. It was developed and marketed in Spain by Inmunotek S.L. Uromune has also been approved in Mexico and the Dominican Republic and is currently pending approval in Canada. The vaccine is under development for use and is available via special-access programs in numerous other countries, including in many European countries, Australia, New Zealand, and Chile, among others. Development and approval in the United States is expected to take longer than other countries. Uromune is also under investigation for other uses besides prevention of uncomplicated recurrent UTIs in adults, as well as readministration following potential waning effectiveness. Uromune is used in the prevention of uncomplicated recurrent UTIs in adults. It is indicated specifically for prevention of recurrent UTIs, defined as ≥3 UTIs in 12 months or ≥2 UTIs within 6 months. The vaccine has been described as highly effective against recurrent UTIs. Uromune is a suspension of selected strains of several whole-cell, heat-killed bacteria, including V121 Escherichia coli (25%), V113 Klebsiella pneumoniae (25%), V125 Enterococcus faecalis (25%), and V127 Proteus vulgaris (25%), in glycerol , sodium chloride , artificial pineapple flavoring, and water. These bacteria together are responsible for most cases of UTIs, with E. coli alone responsible for 52 to 80% of recurrent UTIs. Uromune is thought to increase immunity against these UTI-causing bacteria. The vaccine is self-administered as a sublingual spray with two sprays of 100 μL each given once daily for 3 months. A European phase 3 clinical trial , with results published in 2021 and 2022, found that median 0.0 ( IQR Tooltip interquartile range 0.0–1.0) UTIs occurred with Uromune and median 3.0 UTIs ( IQR 0.5–6.0) occurred with placebo during 9 months following a 3- to 6-month Uromune treatment period in 240 women. There were a total of 249 UTIs with placebo, 80 UTIs with 3-month Uromune (−68% relative to placebo), and 70 UTIs (−72% relative to placebo) with 6-month Uromune during the 9-month period. The 9-month UTI-free rate was 55.7% with 3 months of Uromune treatment and 58.0% with 6 months of Uromune treatment versus 25.0% with placebo. Hence, the UTI-free rate was more than doubled with Uromune in this trial (increased by ~2.3-fold). The median time to first UTI after treatment was 275.0 days with both 3-month and 6-month Uromune relative to 48.0 days with placebo. In subanalyses of the trial, Uromune reduced overall UTI symptoms, resulted in fewer days on antibiotics, and improved total, general, and physical quality of life . A 2020 systematic review identified three clinical studies of Uromune, including a prospective cohort study , a retrospective cohort study , and a retrospective observational study , all conducted in the United Kingdom or Spain. For short-term efficacy (≤6 months), the UTI-free rate with Uromune was 63.5 to 81%, relative to 3 to 5.6% for antibiotic therapy. For long-term efficacy (>6 months), the UTI-free rate was 56.6% and 90.3%, with the longest reported outcome being 56.6% at 15 months, whereas almost all patients given daily antibiotic therapy had experienced at least one UTI by 12 and 15 months. UTI recurrence occurred at median 180 days with Uromune and median 19 days with antibiotic prophylaxis . A subsequent 2023 review of five observational studies with over 1,400 women, including the above studies, reported that Uromune was associated with higher UTI-free rates (35–58%) relative to 6-month antibiotic prophylaxis (0%) in two comparative observational studies and was associated with UTI-free rates of 33 to 78% over 9 to 24 months of follow-up in three uncontrolled prospective observational studies. Likewise, in the five observational studies with 1,408 women, another 2020 systematic review reported UTI-free rates of 35 to 90% with Uromune in 519 women versus rates of 0–9% with antibiotic prophylaxis in 499 women over 15 months. In a preliminary analysis of the Health Canada -approved first-in-North America observational study, findings were comparable to previous observational studies. In this study, which included 25 patients, the UTI rate was reduced by 82% for the 9-month post-vaccination period, with number of UTIs reducing from mean 11.5 UTIs/month to 2.1 UTIs/month, and the UTI-free rate during this period was 48% (12 of 25). At 12 months, 80% of subjects (20 of 25) reported that they were moderately or markedly improved. The preceding results are from the pre- COVID-19 pandemic cohort and an expanded follow-up with 64 women has been conducted with results published. In the expanded cohort, there were a mean of 6.8 UTIs/year pre-vaccination, the UTI-free rate over the 9-month post-vaccination period was 40.6%, the reduction of infection rate was 75.3% for this period relative to the year prior to vaccination, and 80.3% reported being moderately or markedly improved at 12-month follow-up, with 58.1% considering themselves "mostly satisfied, pleased, or delighted". Quality of life scored also improved by 1.5 points in the study. The risk of UTI recurrence with Uromune treatment has been found to increase with time, suggesting that the vaccine gradually wears off. In a 2022 long-term prospective observational study with 1,003 patients, Uromune reduced the number of UTIs to 0–2 in 95.5% at 3 months, in 86.8% at 6 months, and in 54.7% at 12 months. On the basis of these findings, readministration may be warranted and may be studied in the future. However, in a 2024 study that was the first long-term study of Uromune, where 60% of individuals had a single course of Uromune and 40% had repeat courses 1 to 2 years after the first course, 54% of 89 women and men remained UTI-free 5 to 9 years after first receiving the vaccine. As of May 2023, at least eight clinical studies of Uromune, including one phase 3 randomized controlled trial , have been conducted. These studies have included over 2,200 patients. More than 40,000 patients have received Uromune as of 2023, including at least 22,000 in special-access programs. Uromune is used in the prevention of uncomplicated recurrent UTIs in adults. It is indicated specifically for prevention of recurrent UTIs, defined as ≥3 UTIs in 12 months or ≥2 UTIs within 6 months. The vaccine has been described as highly effective against recurrent UTIs. Uromune is a suspension of selected strains of several whole-cell, heat-killed bacteria, including V121 Escherichia coli (25%), V113 Klebsiella pneumoniae (25%), V125 Enterococcus faecalis (25%), and V127 Proteus vulgaris (25%), in glycerol , sodium chloride , artificial pineapple flavoring, and water. These bacteria together are responsible for most cases of UTIs, with E. coli alone responsible for 52 to 80% of recurrent UTIs. Uromune is thought to increase immunity against these UTI-causing bacteria. The vaccine is self-administered as a sublingual spray with two sprays of 100 μL each given once daily for 3 months. A European phase 3 clinical trial , with results published in 2021 and 2022, found that median 0.0 ( IQR Tooltip interquartile range 0.0–1.0) UTIs occurred with Uromune and median 3.0 UTIs ( IQR 0.5–6.0) occurred with placebo during 9 months following a 3- to 6-month Uromune treatment period in 240 women. There were a total of 249 UTIs with placebo, 80 UTIs with 3-month Uromune (−68% relative to placebo), and 70 UTIs (−72% relative to placebo) with 6-month Uromune during the 9-month period. The 9-month UTI-free rate was 55.7% with 3 months of Uromune treatment and 58.0% with 6 months of Uromune treatment versus 25.0% with placebo. Hence, the UTI-free rate was more than doubled with Uromune in this trial (increased by ~2.3-fold). The median time to first UTI after treatment was 275.0 days with both 3-month and 6-month Uromune relative to 48.0 days with placebo. In subanalyses of the trial, Uromune reduced overall UTI symptoms, resulted in fewer days on antibiotics, and improved total, general, and physical quality of life . A 2020 systematic review identified three clinical studies of Uromune, including a prospective cohort study , a retrospective cohort study , and a retrospective observational study , all conducted in the United Kingdom or Spain. For short-term efficacy (≤6 months), the UTI-free rate with Uromune was 63.5 to 81%, relative to 3 to 5.6% for antibiotic therapy. For long-term efficacy (>6 months), the UTI-free rate was 56.6% and 90.3%, with the longest reported outcome being 56.6% at 15 months, whereas almost all patients given daily antibiotic therapy had experienced at least one UTI by 12 and 15 months. UTI recurrence occurred at median 180 days with Uromune and median 19 days with antibiotic prophylaxis . A subsequent 2023 review of five observational studies with over 1,400 women, including the above studies, reported that Uromune was associated with higher UTI-free rates (35–58%) relative to 6-month antibiotic prophylaxis (0%) in two comparative observational studies and was associated with UTI-free rates of 33 to 78% over 9 to 24 months of follow-up in three uncontrolled prospective observational studies. Likewise, in the five observational studies with 1,408 women, another 2020 systematic review reported UTI-free rates of 35 to 90% with Uromune in 519 women versus rates of 0–9% with antibiotic prophylaxis in 499 women over 15 months. In a preliminary analysis of the Health Canada -approved first-in-North America observational study, findings were comparable to previous observational studies. In this study, which included 25 patients, the UTI rate was reduced by 82% for the 9-month post-vaccination period, with number of UTIs reducing from mean 11.5 UTIs/month to 2.1 UTIs/month, and the UTI-free rate during this period was 48% (12 of 25). At 12 months, 80% of subjects (20 of 25) reported that they were moderately or markedly improved. The preceding results are from the pre- COVID-19 pandemic cohort and an expanded follow-up with 64 women has been conducted with results published. In the expanded cohort, there were a mean of 6.8 UTIs/year pre-vaccination, the UTI-free rate over the 9-month post-vaccination period was 40.6%, the reduction of infection rate was 75.3% for this period relative to the year prior to vaccination, and 80.3% reported being moderately or markedly improved at 12-month follow-up, with 58.1% considering themselves "mostly satisfied, pleased, or delighted". Quality of life scored also improved by 1.5 points in the study. The risk of UTI recurrence with Uromune treatment has been found to increase with time, suggesting that the vaccine gradually wears off. In a 2022 long-term prospective observational study with 1,003 patients, Uromune reduced the number of UTIs to 0–2 in 95.5% at 3 months, in 86.8% at 6 months, and in 54.7% at 12 months. On the basis of these findings, readministration may be warranted and may be studied in the future. However, in a 2024 study that was the first long-term study of Uromune, where 60% of individuals had a single course of Uromune and 40% had repeat courses 1 to 2 years after the first course, 54% of 89 women and men remained UTI-free 5 to 9 years after first receiving the vaccine. As of May 2023, at least eight clinical studies of Uromune, including one phase 3 randomized controlled trial , have been conducted. These studies have included over 2,200 patients. More than 40,000 patients have received Uromune as of 2023, including at least 22,000 in special-access programs. Side effects of Uromune are reported to be infrequent and minor. In two comparative studies of Uromune versus antibiotics , no adverse reactions were reported with Uromune. In the United Kingdom prospective study , one serious adverse reaction—an allergic reaction —and seven minor adverse reactions ( post-nasal drip , mouth stinging, scar itching , abdomen itching, abdominal pain , mild nausea , and worsening of asthma ) were reported. In two other studies of 166 and 784 patients, minor side effects including dry mouth (n=8), gastritis (n=4), general illness (n=3), glossitis (n=2), and flare-up of rheumatoid arthritis not thought to be treatment-related (n=1). In the North American clinical study, there were five non-serious adverse reactions and one serious adverse reaction in 25 individuals, with one mild and self-limited adverse reaction deemed potentially vaccine-related. In safety reports of 22,000 patients receiving the vaccine, there were 15 filed reports of adverse reactions for more than 1.5 million doses. In the phase 3 randomized controlled trial of Uromune versus placebo, there were 76 adverse reactions in the 3-month Uromune group, 48 adverse reactions in the 6-month Uromune group, and 81 adverse reactions in the placebo group. The most frequent adverse reactions, occurring in ≥5% of individuals, were chest infections , candidiasis , and vaginitis . The seven serious adverse reactions, which occurred in five individuals, were not considered not related to Uromune. Of the 205 adverse effects reported in the trial, 9 (4.4%), presenting in five individuals (2.2%), were considered to be study intervention-related. This included two in the placebo group (2.6%), three with 3-month Uromune (3.9%), and zero with 6-month Uromune (0.0%). On the basis of these findings, it has been concluded that Uromune may be considered a very safe medical intervention. In the 2020 systematic review , Uromune was described as having acceptable safety and minimal adverse effects. The mechanism of action of Uromune is believed to be induction of antibody production and activation of human dendritic cells to generate T helper (Th) 1 , Th17 , and interleukin-10 , in turn resulting in anti-inflammatory T-cell responses in secondary lymphoid organs and locally in the bladder . It is thought that induction of adaptive immunity following Uromune treatment discontinuation results in lasting clinical protection, although trained immunity may also be involved. Uromune is administered sublingually , which is known to bypass degradation by gastric fluids and gastrointestinal enzymes that occurs with oral administration . Moreover, sublingual administration is thought to have the potential to induce mucosal immune responses in a broad range of tissues , including the genitourinary tract . Accordingly, Uromune has been found to induce immune responses both systemically and in the genitourinary tract. Uromune was first described in the literature by 2012. The vaccine has been available since 2010 in clinical practice. It was developed and marketed in Spain by the pharmaceutical company Immunotek S.L. in Madrid . The vaccine has also since been approved in Mexico and the Dominican Republic . As of October 2023, Uromune is under development for use in other countries and is in the preregistration phase of development, with approval pending in Canada. It is also available for patients through various special-access (compassionate-use) programs in 26 countries. Countries where Uromune is under development or available through early-access programs include Australia, Belgium , Canada, Chile, the Czech Republic , Denmark , Finland , France, Germany, Luxembourg , the Netherlands , New Zealand, Norway , Portugal , Romania , Serbia , Slovakia , Slovenia , Sweden, Turkey , and the United Kingdom, among others. A notable exception among countries is the United States, where more stringent clinical trials are likely to be required before Uromune could be approved or made available. Moreover, a United States-based randomized controlled trial may be required for approval in this country. Development of Uromune has been licensed to Red Leaf Medical. Clinical development of Uromune for prevention of UTIs in elderly people in long-term care homes, in children with recurrent UTIs, and in adults with complicated recurrent UTIs (e.g., patients with catheters or neurogenic bladder ) is in the tentative planning stages. Further assessment of Uromune may also include repeated administration following potential long-term loss of immunity and possible combination with vaccines for related infections. Several other vaccines for recurrent UTIs, including OM-89/UroVaxom ( oral tablet ), Solco-Urovac ( vaginal suppository / intramuscular injection ), and ExPEC4 V (intramuscular injection), are also under development.

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Chikungunya

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Makonde language

Southern Bantoid Bantu Rufiji–Ruvuma Ruvuma Makonde languages Makonde Bantu Rufiji–Ruvuma Ruvuma Makonde languages Makonde Rufiji–Ruvuma Ruvuma Makonde languages Makonde Ruvuma Makonde languages Makonde Makonde languages Makonde Makonde ? Matembwe–Machinga Mabiha Ndonde Hamba (Mawanda) Makonde, or Kimakonde , is the language spoken by the Makonde , an ethnic group in southeast Tanzania and northern Mozambique . Makonde is a central Bantu language closely related to Yao . The Matambwe (Matembwe) and Mabiha (Maviha) dialects are divergent, and may not be Makonde. [ full citation needed ] A mosquito-borne viral fever first identified on the Makonde Plateau is named Chikungunya , which is derived from the Makonde root verb kungunyala (meaning "that which bends up", "to become contorted," or "to walk bent over"). The derivation of the term is generally falsely attributed to Swahili . The following are the consonants and vowels of the Makonde language: There also tends to be a rising final vowel sound /vv́/ within vowel combinations.There also tends to be a rising final vowel sound /vv́/ within vowel combinations.

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Chikungunya

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Chickenpox

Chickenpox , or chicken pox , also known as varicella , [ pronunciation? ] is a highly contagious , vaccine-preventable disease caused by the initial infection with varicella zoster virus (VZV), a member of the herpesvirus family. The disease results in a characteristic skin rash that forms small, itchy blisters , which eventually scab over. It usually starts on the chest, back, and face. It then spreads to the rest of the body. The rash and other symptoms, such as fever , tiredness , and headaches , usually last five to seven days. Complications may occasionally include pneumonia , inflammation of the brain , and bacterial skin infections. The disease is usually more severe in adults than in children. Chickenpox is an airborne disease which easily spreads via human-to-human transmission , typically through the coughs and sneezes of an infected person. The incubation period is 10–21 days, after which the characteristic rash appears. It may be spread from one to two days before the rash appears until all lesions have crusted over. It may also spread through contact with the blisters. Those with shingles may spread chickenpox to those who are not immune through contact with the blisters. The disease can usually be diagnosed based on the presenting symptom; however, in unusual cases it may be confirmed by polymerase chain reaction (PCR) testing of the blister fluid or scabs. Testing for antibodies may be done to determine if a person is immune. People usually only get chickenpox once. Although reinfections by the virus occur, these reinfections usually do not cause any symptoms. Since its introduction in 1995 in the United States, the varicella vaccine has resulted in a decrease in the number of cases and complications from the disease. It protects about 70–90 percent of people from disease with a greater benefit for severe disease. Routine immunization of children is recommended in many countries. Immunization within three days of exposure may improve outcomes in children. Treatment of those infected may include calamine lotion to help with itching, keeping the fingernails short to decrease injury from scratching, and the use of paracetamol (acetaminophen) to help with fevers. For those at increased risk of complications, antiviral medication such as aciclovir is recommended. Chickenpox occurs in all parts of the world. In 2013, there were 140 million cases of chickenpox and shingles worldwide. Before routine immunization the number of cases occurring each year was similar to the number of people born. Since immunization the number of infections in the United States has decreased nearly 90%. In 2015 chickenpox resulted in 6,400 deaths globally – down from 8,900 in 1990. Death occurs in about 1 per 60,000 cases. Chickenpox was not separated from smallpox until the late 19th century. In 1888 its connection to shingles was determined. The first documented use of the term chicken pox was in 1658. Various explanations have been suggested for the use of "chicken" in the name, one being the relative mildness of the disease. The early ( prodromal ) symptoms in adolescents and adults are nausea, loss of appetite, aching muscles, and headache. This is followed by the characteristic rash or oral sores, malaise , and a low-grade fever that signal the presence of the disease. Oral manifestations of the disease (enanthem) not uncommonly may precede the external rash (exanthem). In children the illness is not usually preceded by prodromal symptoms, and the first sign is the rash or the spots in the oral cavity. The rash begins as small red dots on the face, scalp, torso, upper arms and legs; progressing over 10–12 hours to small bumps, blisters and pustules ; followed by umbilication and the formation of scabs. At the blister stage, intense itching is usually present. Blisters may also occur on the palms, soles, and genital area. Commonly, visible evidence of the disease develops in the oral cavity and tonsil areas in the form of small ulcers which can be painful or itchy or both; this enanthem (internal rash) can precede the exanthem (external rash) by 1 to 3 days or can be concurrent. These symptoms of chickenpox appear 10 to 21 days after exposure to a contagious person. Adults may have a more widespread rash and longer fever, and they are more likely to experience complications, such as varicella pneumonia . Because watery nasal discharge containing live virus usually precedes both exanthem (external rash) and enanthem (oral ulcers) by 1 to 2 days, the infected person actually becomes contagious one to two days before recognition of the disease. Contagiousness persists until all vesicular lesions have become dry crusts (scabs), which usually entails four or five days, by which time nasal shedding of live virus ceases. The condition usually resolves by itself within a week or two. The rash may, however, last for up to one month. [ medical citation needed ] Chickenpox is rarely fatal, although it is generally more severe in adult men than in women or children. Non-immune pregnant women and those with a suppressed immune system are at highest risk of serious complications. Arterial ischemic stroke (AIS) associated with chickenpox in the previous year accounts for nearly one third of childhood AIS. The most common late complication of chickenpox is shingles (herpes zoster), caused by reactivation of the varicella zoster virus decades after the initial, often childhood, chickenpox infection. During pregnancy the dangers to the fetus associated with a primary VZV infection are greater in the first six months. In the third trimester, the mother is more likely to have severe symptoms. For pregnant women, antibodies produced as a result of immunization or previous infection are transferred via the placenta to the fetus . Varicella infection in pregnant women could lead to spread via the placenta and infection of the fetus. If infection occurs during the first 28 weeks of gestation , this can lead to fetal varicella syndrome (also known as congenital varicella syndrome ). Effects on the fetus can range in severity from underdeveloped toes and fingers to severe anal and bladder malformation. Possible problems include: Infection late in gestation or immediately following birth is referred to as " neonatal varicella ". Maternal infection is associated with premature delivery. The risk of the baby developing the disease is greatest following exposure to infection in the period 7 days before delivery and up to 8 days following the birth. The baby may also be exposed to the virus via infectious siblings or other contacts, but this is of less concern if the mother is immune. Newborns who develop symptoms are at a high risk of pneumonia and other serious complications of the disease. During pregnancy the dangers to the fetus associated with a primary VZV infection are greater in the first six months. In the third trimester, the mother is more likely to have severe symptoms. For pregnant women, antibodies produced as a result of immunization or previous infection are transferred via the placenta to the fetus . Varicella infection in pregnant women could lead to spread via the placenta and infection of the fetus. If infection occurs during the first 28 weeks of gestation , this can lead to fetal varicella syndrome (also known as congenital varicella syndrome ). Effects on the fetus can range in severity from underdeveloped toes and fingers to severe anal and bladder malformation. Possible problems include: Infection late in gestation or immediately following birth is referred to as " neonatal varicella ". Maternal infection is associated with premature delivery. The risk of the baby developing the disease is greatest following exposure to infection in the period 7 days before delivery and up to 8 days following the birth. The baby may also be exposed to the virus via infectious siblings or other contacts, but this is of less concern if the mother is immune. Newborns who develop symptoms are at a high risk of pneumonia and other serious complications of the disease. Exposure to VZV in a healthy child initiates the production of host immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) antibodies; IgG antibodies persist for life and confer immunity. Cell-mediated immune responses are also important in limiting the scope and the duration of primary varicella infection. After primary infection, VZV is hypothesized to spread from mucosal and epidermal lesions to local sensory nerves . VZV then remains latent in the dorsal ganglion cells of the sensory nerves. Reactivation of VZV results in the clinically distinct syndrome of herpes zoster (i.e., shingles ), postherpetic neuralgia , and sometimes Ramsay Hunt syndrome type II . Varicella zoster can affect the arteries in the neck and head, producing stroke, either during childhood, or after a latency period of many years. After a chickenpox infection, the virus remains dormant in the body's nerve tissues for about 50 years. This, however, does not mean that VZV cannot be contracted later in life. The immune system usually keeps the virus at bay, but it can still manifest itself at any given age causing a different form of the viral infection called shingles (also known as herpes zoster). Since the efficacy of the human immune system decreases with age, the United States Advisory Committee on Immunization Practices (ACIP) suggests that every adult over the age of 50 years get the herpes zoster vaccine. Shingles affects one in five adults infected with chickenpox as children, especially those who are immune-suppressed, particularly from cancer, HIV, or other conditions. Stress can bring on shingles as well, although scientists are still researching the connection. Adults over the age of 60 who had chickenpox but not shingles are the most prone age demographic. After a chickenpox infection, the virus remains dormant in the body's nerve tissues for about 50 years. This, however, does not mean that VZV cannot be contracted later in life. The immune system usually keeps the virus at bay, but it can still manifest itself at any given age causing a different form of the viral infection called shingles (also known as herpes zoster). Since the efficacy of the human immune system decreases with age, the United States Advisory Committee on Immunization Practices (ACIP) suggests that every adult over the age of 50 years get the herpes zoster vaccine. Shingles affects one in five adults infected with chickenpox as children, especially those who are immune-suppressed, particularly from cancer, HIV, or other conditions. Stress can bring on shingles as well, although scientists are still researching the connection. Adults over the age of 60 who had chickenpox but not shingles are the most prone age demographic. The diagnosis of chickenpox is primarily based on the signs and symptoms, with typical early symptoms followed by a characteristic rash . Confirmation of the diagnosis is by examination of the fluid within the vesicles of the rash, or by testing blood for evidence of an acute immunologic response. Vesicular fluid can be examined with a Tzanck smear , or by testing for direct fluorescent antibody . The fluid can also be "cultured", whereby attempts are made to grow the virus from a fluid sample. Blood tests can be used to identify a response to acute infection (IgM) or previous infection and subsequent immunity (IgG). Prenatal diagnosis of fetal varicella infection can be performed using ultrasound , though a delay of 5 weeks following primary maternal infection is advised. A PCR (DNA) test of the mother's amniotic fluid can also be performed, though the risk of spontaneous abortion due to the amniocentesis procedure is higher than the risk of the baby's developing fetal varicella syndrome. The spread of chickenpox can be prevented by isolating affected individuals. Contagion is by exposure to respiratory droplets, or direct contact with lesions, within a period lasting from three days before the onset of the rash, to four days after the onset of the rash. As with all respiratory pathogens once presumed to transmit via respiratory droplets, it is highly likely to be carried by the aerosols generated during routine breathing, talking, and even singing. The chickenpox virus is susceptible to disinfectants, notably chlorine bleach (i.e., sodium hypochlorite ). Like all enveloped viruses , it is sensitive to drying, heat and detergents. Chickenpox can be prevented by vaccination. The side effects are usually mild, such as some pain or swelling at the injection site . A live attenuated varicella vaccine, the Oka strain, was developed by Michiaki Takahashi and his colleagues in Japan in the early 1970s. In 1995, Merck & Co. licensed the "Oka" strain of the varicella virus in the United States , and Maurice Hilleman 's team at Merck invented a varicella vaccine in the same year. The varicella vaccine is recommended in many countries. Some countries require the varicella vaccination or an exemption before entering elementary school. A second dose is recommended five years after the initial immunization. A vaccinated person is likely to have a milder case of chickenpox if they become infected. Immunization within three days following household contact reduces infection rates and severity in children. Being exposed to chickenpox as an adult (for example, through contact with infected children) may boost immunity to shingles. Therefore, it was thought that when the majority of children were vaccinated against chickenpox, adults might lose this natural boosting, so immunity would drop and more shingles cases would occur. On the other hand, current observations suggest that exposure to children with varicella is not a critical factor in the maintenance of immunity. Multiple subclinical reactivations of varicella zoster virus may occur spontaneously and, despite not causing clinical disease, may still provide an endogenous boost to immunity against zoster. The vaccine is part of the routine immunization schedule in the US. Some European countries include it as part of universal vaccinations in children, but not all countries provide the vaccine. In the UK as of 2014, the vaccine is only recommended in people who are particularly vulnerable to chickenpox. This is to keep the virus in circulation, thereby exposing the population to the virus at an early age, when it is less harmful, and to reduce the occurrence of shingles through repeated exposure to the virus later in life. In November 2023, the UK Joint Committee on Vaccination and Immunisation recommended all children be given the vaccine at ages 12 months and 18 months; however, this has not yet been implemented. In populations that have not been immunized or if immunity is questionable, a clinician may order an enzyme immunoassay . An immunoassay measures the levels of antibodies against the virus that give immunity to a person. If the levels of antibodies are low (low titer) or questionable, reimmunization may be done. The spread of chickenpox can be prevented by isolating affected individuals. Contagion is by exposure to respiratory droplets, or direct contact with lesions, within a period lasting from three days before the onset of the rash, to four days after the onset of the rash. As with all respiratory pathogens once presumed to transmit via respiratory droplets, it is highly likely to be carried by the aerosols generated during routine breathing, talking, and even singing. The chickenpox virus is susceptible to disinfectants, notably chlorine bleach (i.e., sodium hypochlorite ). Like all enveloped viruses , it is sensitive to drying, heat and detergents. Chickenpox can be prevented by vaccination. The side effects are usually mild, such as some pain or swelling at the injection site . A live attenuated varicella vaccine, the Oka strain, was developed by Michiaki Takahashi and his colleagues in Japan in the early 1970s. In 1995, Merck & Co. licensed the "Oka" strain of the varicella virus in the United States , and Maurice Hilleman 's team at Merck invented a varicella vaccine in the same year. The varicella vaccine is recommended in many countries. Some countries require the varicella vaccination or an exemption before entering elementary school. A second dose is recommended five years after the initial immunization. A vaccinated person is likely to have a milder case of chickenpox if they become infected. Immunization within three days following household contact reduces infection rates and severity in children. Being exposed to chickenpox as an adult (for example, through contact with infected children) may boost immunity to shingles. Therefore, it was thought that when the majority of children were vaccinated against chickenpox, adults might lose this natural boosting, so immunity would drop and more shingles cases would occur. On the other hand, current observations suggest that exposure to children with varicella is not a critical factor in the maintenance of immunity. Multiple subclinical reactivations of varicella zoster virus may occur spontaneously and, despite not causing clinical disease, may still provide an endogenous boost to immunity against zoster. The vaccine is part of the routine immunization schedule in the US. Some European countries include it as part of universal vaccinations in children, but not all countries provide the vaccine. In the UK as of 2014, the vaccine is only recommended in people who are particularly vulnerable to chickenpox. This is to keep the virus in circulation, thereby exposing the population to the virus at an early age, when it is less harmful, and to reduce the occurrence of shingles through repeated exposure to the virus later in life. In November 2023, the UK Joint Committee on Vaccination and Immunisation recommended all children be given the vaccine at ages 12 months and 18 months; however, this has not yet been implemented. In populations that have not been immunized or if immunity is questionable, a clinician may order an enzyme immunoassay . An immunoassay measures the levels of antibodies against the virus that give immunity to a person. If the levels of antibodies are low (low titer) or questionable, reimmunization may be done. Treatment mainly consists of easing the symptoms. As a protective measure, people are usually required to stay at home while they are infectious to avoid spreading the disease to others. Cutting the fingernails short or wearing gloves may prevent scratching and minimize the risk of secondary infections . Although there have been no formal clinical studies evaluating the effectiveness of topical application of calamine lotion (a topical barrier preparation containing zinc oxide , and one of the most commonly used interventions), it has an excellent safety profile. Maintaining good hygiene and daily cleaning of skin with warm water can help to avoid secondary bacterial infection ; scratching may increase the risk of secondary infection. Paracetamol (acetaminophen) but not aspirin may be used to reduce fever. Aspirin use by someone with chickenpox may cause serious, sometimes fatal disease of the liver and brain, Reye syndrome . People at risk of developing severe complications who have had significant exposure to the virus may be given intra-muscular varicella zoster immune globulin (VZIG), a preparation containing high titres of antibodies to varicella zoster virus, to ward off the disease. Antivirals are sometimes used. If aciclovir by mouth is started within 24 hours of rash onset, it decreases symptoms by one day but has no effect on complication rates. Use of aciclovir therefore is not currently recommended for individuals with normal immune function. Children younger than 12 years old and older than one month are not meant to receive antiviral drugs unless they have another medical condition which puts them at risk of developing complications. Treatment of chickenpox in children is aimed at symptoms while the immune system deals with the virus. With children younger than 12 years, cutting fingernails and keeping them clean is an important part of treatment as they are more likely to scratch their blisters more deeply than adults. Aspirin is highly contraindicated in children younger than 16 years, as it has been related to Reye syndrome. Infection in otherwise healthy adults tends to be more severe. Treatment with antiviral drugs (e.g. aciclovir or valaciclovir ) is generally advised, as long as it is started within 24–48 hours from rash onset. Remedies to ease the symptoms of chickenpox in adults are basically the same as those used for children. Adults are more often prescribed antiviral medication, as it is effective in reducing the severity of the condition and the likelihood of developing complications. Adults are advised to increase water intake to reduce dehydration and to relieve headaches. Painkillers such as paracetamol (acetaminophen) are recommended, as they are effective in relieving itching and other symptoms such as fever or pains. Antihistamines relieve itching and may be used in cases where the itching prevents sleep, because they also act as a sedative . As with children, antiviral medication is considered more useful for those adults who are more prone to develop complications. These include pregnant women or people who have a weakened immune system. If aciclovir by mouth is started within 24 hours of rash onset, it decreases symptoms by one day but has no effect on complication rates. Use of aciclovir therefore is not currently recommended for individuals with normal immune function. Children younger than 12 years old and older than one month are not meant to receive antiviral drugs unless they have another medical condition which puts them at risk of developing complications. Treatment of chickenpox in children is aimed at symptoms while the immune system deals with the virus. With children younger than 12 years, cutting fingernails and keeping them clean is an important part of treatment as they are more likely to scratch their blisters more deeply than adults. Aspirin is highly contraindicated in children younger than 16 years, as it has been related to Reye syndrome. Infection in otherwise healthy adults tends to be more severe. Treatment with antiviral drugs (e.g. aciclovir or valaciclovir ) is generally advised, as long as it is started within 24–48 hours from rash onset. Remedies to ease the symptoms of chickenpox in adults are basically the same as those used for children. Adults are more often prescribed antiviral medication, as it is effective in reducing the severity of the condition and the likelihood of developing complications. Adults are advised to increase water intake to reduce dehydration and to relieve headaches. Painkillers such as paracetamol (acetaminophen) are recommended, as they are effective in relieving itching and other symptoms such as fever or pains. Antihistamines relieve itching and may be used in cases where the itching prevents sleep, because they also act as a sedative . As with children, antiviral medication is considered more useful for those adults who are more prone to develop complications. These include pregnant women or people who have a weakened immune system. The duration of the visible blistering caused by varicella zoster virus varies in children usually from four to seven days, and the appearance of new blisters begins to subside after the fifth day. Chickenpox infection is milder in young children, and symptomatic treatment, with sodium bicarbonate baths or antihistamine medication may ease itching. In adults, the disease is more severe, though the incidence is much less common. Infection in adults is associated with greater morbidity and mortality due to pneumonia (either direct viral pneumonia or secondary bacterial pneumonia ), bronchitis (either viral bronchitis or secondary bacterial bronchitis), hepatitis, and encephalitis. In particular, up to 10% of pregnant women with chickenpox develop pneumonia, the severity of which increases with onset later in gestation. In England and Wales, 75% of deaths due to chickenpox are in adults. Inflammation of the brain, encephalitis, can occur in immunocompromised individuals, although the risk is higher with herpes zoster. Necrotizing fasciitis is also a rare complication. Varicella can be lethal to individuals with impaired immunity. The number of people in this high-risk group has increased, due to the HIV epidemic and the increased use of immunosuppressive therapies. Varicella is a particular problem in hospitals when there are patients with immune systems weakened by drugs (e.g., high-dose steroids) or HIV . Secondary bacterial infection of skin lesions, manifesting as impetigo , cellulitis , and erysipelas , is the most common complication in healthy children. Disseminated primary varicella infection usually seen in the immunocompromised may have high morbidity. Ninety percent of cases of varicella pneumonia occur in the adult population. Rarer complications of disseminated chickenpox include myocarditis , hepatitis , and glomerulonephritis . Hemorrhagic complications are more common in the immunocompromised or immunosuppressed populations, although healthy children and adults have been affected. Five major clinical syndromes have been described: febrile purpura, malignant chickenpox with purpura , postinfectious purpura, purpura fulminans , and anaphylactoid purpura . These syndromes have variable courses, with febrile purpura being the most benign of the syndromes and having an uncomplicated outcome. In contrast, malignant chickenpox with purpura is a grave clinical condition that has a mortality rate of greater than 70%. The cause of these hemorrhagic chickenpox syndromes is not known. Primary varicella occurs in all countries worldwide. In 2015 chickenpox resulted in 6,400 deaths globally – down from 8,900 in 1990. There were 7,000 deaths in 2013. Varicella is highly transmissible, with an infection rate of 90% in close contacts. In temperate countries, chickenpox is primarily a disease of children, with most cases occurring during the winter and spring, most likely due to school contact. In such countries it is one of the classic diseases of childhood , with most cases occurring in children up to age 15; most people become infected before adulthood, and 10% of young adults remain susceptible. In the United States, a temperate country, the Centers for Disease Control and Prevention (CDC) do not require state health departments to report infections of chickenpox, and only 31 states volunteered this information as of 2013 [ update ] . A 2013 study conducted by the social media disease surveillance tool called Sickweather used anecdotal reports of chickenpox infections on social media systems Facebook and Twitter to measure and rank states with the most infections per capita, with Maryland, Tennessee and Illinois in the top three. In the tropics, chickenpox often occurs in older people and may cause more serious disease. In adults, the pock marks are darker and the scars more prominent than in children. How the term chickenpox originated is not clear but it may be due to it being a relatively mild disease. It has been said to be derived from chickpeas , based on resemblance of the vesicles to chickpeas, or to come from the rash resembling chicken pecks. Other suggestions include the designation chicken for a child (i.e., literally 'child pox'), a corruption of itching-pox , or the idea that the disease may have originated in chickens. Samuel Johnson explained the designation as "from its being of no very great danger". Because chickenpox is usually more severe in adults than it is in children, some parents deliberately expose their children to the virus, for example by taking them to " chickenpox parties ". Doctors say that children are safer getting the vaccine, which is a weakened form of the virus, than getting the disease, which can be fatal or lead to shingles later in life. Repeated exposure to chickenpox may protect against zoster. How the term chickenpox originated is not clear but it may be due to it being a relatively mild disease. It has been said to be derived from chickpeas , based on resemblance of the vesicles to chickpeas, or to come from the rash resembling chicken pecks. Other suggestions include the designation chicken for a child (i.e., literally 'child pox'), a corruption of itching-pox , or the idea that the disease may have originated in chickens. Samuel Johnson explained the designation as "from its being of no very great danger". Because chickenpox is usually more severe in adults than it is in children, some parents deliberately expose their children to the virus, for example by taking them to " chickenpox parties ". Doctors say that children are safer getting the vaccine, which is a weakened form of the virus, than getting the disease, which can be fatal or lead to shingles later in life. Repeated exposure to chickenpox may protect against zoster. Humans are the only known species that the disease affects naturally. However, chickenpox has been caused in animals, including chimpanzees and gorillas . Sorivudine , a nucleoside analog, has been reported to be effective in the treatment of primary varicella in healthy adults (case reports only), but large-scale clinical trials are still needed to demonstrate its efficacy. There was speculation in 2005 that continuous dosing of aciclovir by mouth for a period of time could eradicate VZV from the host, although further trials were required to discern whether eradication was actually viable.

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Réunion

Réunion , [note 1] officially Department of Réunion , [note 2] is an island in the Indian Ocean that is an overseas department and region of France. Part of the Mascarene Islands , it is located approximately 679 km (422 mi) east of the island of Madagascar and 175 km (109 mi) southwest of the island of Mauritius . As of January 2024 [ update ] , it had a population of 885,700. Its capital and largest city is Saint-Denis . Réunion was uninhabited until French immigrants and colonial subjects settled the island in the 17th century. Its tropical climate led to the development of a plantation economy focused primarily on sugar; slaves from East Africa were imported as fieldworkers, followed by Malays, Vietnamese , Chinese, and Indians as indentured laborers. Today, the greatest proportion of the population is of mixed descent, while the predominant language is Réunion Creole , though French remains the sole official language. Since 1946, Réunion has been governed as a French region and thus has a similar status to its counterparts in Metropolitan France. Consequently, it is one of the outermost regions of the European Union and part of the eurozone ; it is, along with the French overseas department of Mayotte , one of the two eurozone areas in the Southern Hemisphere . Owing to its strategic location, France maintains a large military presence.France took possession of the island in the 17th century, naming it Bourbon , after the dynasty that then ruled France. To break with this name, which was too attached to the Ancien Régime , the National Convention decided on 23 March 1793 to rename the territory Réunion Island. ("Réunion", in French, usually means "meeting" or "assembly" rather than "reunion". This name was presumably chosen in homage to the meeting of the fédérés of Marseilles and the Paris National Guards that preceded the insurrection of 10 August 1792 . No document establishes this and the use of the word "meeting" could have been purely symbolic.) The island changed its name again in the 19th century: in 1806, under the First Empire , General Decaen named it Île Bonaparte (after Napoleon ), and in 1810 it became Île Bourbon again. It was eventually renamed Réunion after the fall of the July monarchy by a decree of the provisional government on 7 March 1848. In accordance with the original spelling and the classical spelling and typographical rules, "la Réunion" was written with a lower case in the article, but during the end of the 20th century, the spelling "La Réunion" with a capital letter was developed in many writings to emphasize the integration of the article in the name. This last spelling corresponds to the recommendations of the Commission nationale de toponymie and appears in the current Constitution of the French Republic in articles 72-3 and 73.The island has been inhabited since the 17th century, when people from France and Madagascar settled there. Slavery was abolished on 20 December 1848 (a date celebrated yearly on the island), when the Second Republic abolished slavery in the French colonies. However, indentured workers continued to be brought to Réunion from South India , among other places. The island became an overseas department of France in 1946. Not much is known of Réunion's history prior to the arrival of the Portuguese in the early 16th century. Arab traders were familiar with it by the name Dina Morgabin , "Western Island" (likely Arabic : دنية/دبية ٠غربي Daniyah /Dībah Maghribīy ). The island is possibly featured on a map from 1153 AD by Al Sharif el-Edrisi . [ citation needed ] The island might also have been visited by Swahili or Austronesian (ancient Indonesian–Malaysian) sailors on their journey to the west from the Malay Archipelago to Madagascar. The first European discovery of the area was made around 1507 by Portuguese explorer Diogo Fernandes Pereira , but the specifics are unclear. The uninhabited island might have been first sighted by the expedition led by Dom Pedro Mascarenhas , who gave his name to the island group around Réunion, the Mascarenes . Réunion itself was dubbed Santa Apolónia after a favourite saint , which suggests that the date of the Portuguese discovery could have been 9 February, her feast day. Diogo Lopes de Sequeira is said to have landed on the islands of Réunion and Rodrigues in 1509. [ citation needed ] By the early 1600s, nominal Portuguese rule had left Santa Apolónia virtually untouched. The island was then occupied by France and administered from Port Louis , Mauritius. Although the first French claims date from 1638, when François Cauche [ fr ] and Salomon Goubert visited in June 1638, the island was officially claimed by Jacques Pronis [ fr ] of France in 1642, when he deported a dozen French mutineers to the island from Madagascar . The convicts were returned to France several years later, and in 1649, the island was named Île Bourbon after the French royal House of Bourbon . Colonisation started in 1665, when the French East India Company sent the first settlers. The French colonists developed a plantation economy founded on the cultivation of coffee and sugar by use of slave labor. From the 17th to the 19th centuries, French colonisation, supplemented by importing Africans, Chinese and Indians as workers, contributed to ethnic diversity in the population. From 1690, most of the non-Europeans on the island were enslaved. Of the 80,000 slaves imported to Réunion and Mauritius between 1769 and 1793, 45 % was provided by slave traders of the Sakalava people in North West Madagascar, who raided East Africa and the Comoros for slaves, and the rest was provided by Arab slave traders who bought slaves from Portuguese Mozambique and transported them to Réunion via Madagascar. On 19 March 1793, during the French Revolution , the island's name was changed to "Réunion Island" in homage to the meeting of the Federates of Marseille and the National Guards of Paris, during the march on the Tuileries Palace on 10 August 1792, and to erase the name of the Bourbon dynasty. The abolition of slavery voted by the National Convention on 4 February 1794, was rejected by Réunion, as well as by Île de France (Mauritius). A delegation accompanied by military forces, charged with imposing the liberation of slaves, arrived on the island of Bourbon on 18 June 1796, only to be immediately expelled without mercy. There followed a period of unrest and challenges to the power of the metropolis , which no longer had any authority over the two islands. The First Consul of the Republic, Napoleon Bonaparte , maintained slavery there, which was never abolished in practice, with the law of 20 May 1802. On 26 September 1806, the island took the name of Bonaparte and found itself in the front line of the Franco-British conflict for the control of the Indian Ocean. Following climatic catastrophes of 1806-1807 (cyclones, floods), coffee cultivation declined rapidly and was replaced by sugar cane , whose demand in France increased, due to France's recent loss of Saint-Domingue , and soon of the Île-de-France (Mauritius). Because of its growth cycle, sugarcane is not affected by cyclones. During the Napoleonic Wars , the island was invaded by British forces and its governor, General Sainte-Suzanne, was forced to capitulate on 9 July 1810. The island then came under British rule and was under British occupation until the end of the Napoleonic period. Réunion was returned to the French under the Treaty of Paris of 1814. The slave trade operated openly again after the British occupation, and despite international condemnation, Réunion imported 2,000 slaves every month during the 1820s, mostly from the Arab Swahili coast or Quelimane in Portuguese Mozambique. In 1841, Edmond Albius' discovery of hand-pollination of vanilla flowers enabled the island to soon become the world's leading vanilla producer. The cultivation of geranium, whose essence is widely used in perfumery, also took off. From 1838 to 1841, Rear Admiral Anne Chrétien Louis de Hell was governor of the island. A profound change of society and mentality linked to the events of the last ten years led the governor to present three emancipation projects to the Colonial Council. On 20 December 1848, Joseph Napoléon Sébastien Sarda Garriga finally proclaimed the abolition of slavery (20 December was a holiday in Réunion). Louis Henri Hubert Delisle became its first Creole governor on 8 August 1852, and remained in this position until 8 January 1858. After abolition, many of the foreign workers came as indentured workers . Slavery was replaced by a system of contract labor known as engagés , which lasted 1848-1864. In practice, an illegal slave trade was conducted in which slaves were aquired from Portuguese Mozambique and the Zanzibar slave trade and then trafficked to Réunion via the Comoros slave trade , officially called engagés-workers to avoid the British Anti-Slavery Patrol. The opening of the Suez Canal in 1869 reduced the importance of the island as a stopover on the East Indies trade route and caused a shift in commercial traffic away from the island. Europe increasingly turned to sugar beet to meet its sugar needs. Despite the development policy of the local authorities and the recourse to compromise, the economic crisis became evident from the 1870s onwards. However, this economic depression did not prevent the modernization of the island, with the development of the road network, the creation of the railroad and the construction of the artificial harbor of the Pointe des Galets. These major construction projects offered a welcome alternative for agricultural workers. During the Second World War , Réunion was under the authority of the Vichy regime until 30 November 1942, when Free French forces took over the island with the destroyer Léopard . [ citation needed ] Réunion became a département d'outre-mer (overseas département ) of France on 19 March 1946. INSEE assigned to Réunion the department code 974 , and the region code 04 when regional councils were created in 1982 in France, including in existing overseas departments which also became overseas regions. Over about two decades in the late 20th century (1963–1982), 1,630 children from Réunion were relocated to rural areas of metropolitan France , particularly to Creuse , ostensibly for education and work opportunities. That program was led by influential Gaullist politician Michel Debré , who was an MP for Réunion at the time. Many of these children were abused or disadvantaged by the families with whom they were placed. Known as the Children of Creuse , they and their fate came to light in 2002 when one of them, Jean-Jacques Martial, filed suit against the French state for kidnapping and deportation of a minor. Other similar lawsuits were filed over the following years, but all were dismissed by French courts and finally by the European Court of Human Rights in 2011. In 2005 and 2006, Réunion was hit by a crippling epidemic of chikungunya , a disease spread by mosquitoes. According to the BBC News , 255,000 people on Réunion had contracted the disease as of 26 April 2006. The neighbouring islands of Mauritius and Madagascar also suffered epidemics of this disease during the same year. A few cases also appeared in mainland France, carried by people travelling by airline. The French government of Dominique de Villepin sent an emergency aid package worth €36 million and deployed about 500 troops in an effort to eradicate mosquitoes on the island. [ citation needed ]Not much is known of Réunion's history prior to the arrival of the Portuguese in the early 16th century. Arab traders were familiar with it by the name Dina Morgabin , "Western Island" (likely Arabic : دنية/دبية ٠غربي Daniyah /Dībah Maghribīy ). The island is possibly featured on a map from 1153 AD by Al Sharif el-Edrisi . [ citation needed ] The island might also have been visited by Swahili or Austronesian (ancient Indonesian–Malaysian) sailors on their journey to the west from the Malay Archipelago to Madagascar. The first European discovery of the area was made around 1507 by Portuguese explorer Diogo Fernandes Pereira , but the specifics are unclear. The uninhabited island might have been first sighted by the expedition led by Dom Pedro Mascarenhas , who gave his name to the island group around Réunion, the Mascarenes . Réunion itself was dubbed Santa Apolónia after a favourite saint , which suggests that the date of the Portuguese discovery could have been 9 February, her feast day. Diogo Lopes de Sequeira is said to have landed on the islands of Réunion and Rodrigues in 1509. [ citation needed ]By the early 1600s, nominal Portuguese rule had left Santa Apolónia virtually untouched. The island was then occupied by France and administered from Port Louis , Mauritius. Although the first French claims date from 1638, when François Cauche [ fr ] and Salomon Goubert visited in June 1638, the island was officially claimed by Jacques Pronis [ fr ] of France in 1642, when he deported a dozen French mutineers to the island from Madagascar . The convicts were returned to France several years later, and in 1649, the island was named Île Bourbon after the French royal House of Bourbon . Colonisation started in 1665, when the French East India Company sent the first settlers. The French colonists developed a plantation economy founded on the cultivation of coffee and sugar by use of slave labor. From the 17th to the 19th centuries, French colonisation, supplemented by importing Africans, Chinese and Indians as workers, contributed to ethnic diversity in the population. From 1690, most of the non-Europeans on the island were enslaved. Of the 80,000 slaves imported to Réunion and Mauritius between 1769 and 1793, 45 % was provided by slave traders of the Sakalava people in North West Madagascar, who raided East Africa and the Comoros for slaves, and the rest was provided by Arab slave traders who bought slaves from Portuguese Mozambique and transported them to Réunion via Madagascar. On 19 March 1793, during the French Revolution , the island's name was changed to "Réunion Island" in homage to the meeting of the Federates of Marseille and the National Guards of Paris, during the march on the Tuileries Palace on 10 August 1792, and to erase the name of the Bourbon dynasty. The abolition of slavery voted by the National Convention on 4 February 1794, was rejected by Réunion, as well as by Île de France (Mauritius). A delegation accompanied by military forces, charged with imposing the liberation of slaves, arrived on the island of Bourbon on 18 June 1796, only to be immediately expelled without mercy. There followed a period of unrest and challenges to the power of the metropolis , which no longer had any authority over the two islands. The First Consul of the Republic, Napoleon Bonaparte , maintained slavery there, which was never abolished in practice, with the law of 20 May 1802. On 26 September 1806, the island took the name of Bonaparte and found itself in the front line of the Franco-British conflict for the control of the Indian Ocean. Following climatic catastrophes of 1806-1807 (cyclones, floods), coffee cultivation declined rapidly and was replaced by sugar cane , whose demand in France increased, due to France's recent loss of Saint-Domingue , and soon of the Île-de-France (Mauritius). Because of its growth cycle, sugarcane is not affected by cyclones. During the Napoleonic Wars , the island was invaded by British forces and its governor, General Sainte-Suzanne, was forced to capitulate on 9 July 1810. The island then came under British rule and was under British occupation until the end of the Napoleonic period.Réunion was returned to the French under the Treaty of Paris of 1814. The slave trade operated openly again after the British occupation, and despite international condemnation, Réunion imported 2,000 slaves every month during the 1820s, mostly from the Arab Swahili coast or Quelimane in Portuguese Mozambique. In 1841, Edmond Albius' discovery of hand-pollination of vanilla flowers enabled the island to soon become the world's leading vanilla producer. The cultivation of geranium, whose essence is widely used in perfumery, also took off. From 1838 to 1841, Rear Admiral Anne Chrétien Louis de Hell was governor of the island. A profound change of society and mentality linked to the events of the last ten years led the governor to present three emancipation projects to the Colonial Council. On 20 December 1848, Joseph Napoléon Sébastien Sarda Garriga finally proclaimed the abolition of slavery (20 December was a holiday in Réunion). Louis Henri Hubert Delisle became its first Creole governor on 8 August 1852, and remained in this position until 8 January 1858. After abolition, many of the foreign workers came as indentured workers . Slavery was replaced by a system of contract labor known as engagés , which lasted 1848-1864. In practice, an illegal slave trade was conducted in which slaves were aquired from Portuguese Mozambique and the Zanzibar slave trade and then trafficked to Réunion via the Comoros slave trade , officially called engagés-workers to avoid the British Anti-Slavery Patrol. The opening of the Suez Canal in 1869 reduced the importance of the island as a stopover on the East Indies trade route and caused a shift in commercial traffic away from the island. Europe increasingly turned to sugar beet to meet its sugar needs. Despite the development policy of the local authorities and the recourse to compromise, the economic crisis became evident from the 1870s onwards. However, this economic depression did not prevent the modernization of the island, with the development of the road network, the creation of the railroad and the construction of the artificial harbor of the Pointe des Galets. These major construction projects offered a welcome alternative for agricultural workers. During the Second World War , Réunion was under the authority of the Vichy regime until 30 November 1942, when Free French forces took over the island with the destroyer Léopard . [ citation needed ]Réunion became a département d'outre-mer (overseas département ) of France on 19 March 1946. INSEE assigned to Réunion the department code 974 , and the region code 04 when regional councils were created in 1982 in France, including in existing overseas departments which also became overseas regions. Over about two decades in the late 20th century (1963–1982), 1,630 children from Réunion were relocated to rural areas of metropolitan France , particularly to Creuse , ostensibly for education and work opportunities. That program was led by influential Gaullist politician Michel Debré , who was an MP for Réunion at the time. Many of these children were abused or disadvantaged by the families with whom they were placed. Known as the Children of Creuse , they and their fate came to light in 2002 when one of them, Jean-Jacques Martial, filed suit against the French state for kidnapping and deportation of a minor. Other similar lawsuits were filed over the following years, but all were dismissed by French courts and finally by the European Court of Human Rights in 2011. In 2005 and 2006, Réunion was hit by a crippling epidemic of chikungunya , a disease spread by mosquitoes. According to the BBC News , 255,000 people on Réunion had contracted the disease as of 26 April 2006. The neighbouring islands of Mauritius and Madagascar also suffered epidemics of this disease during the same year. A few cases also appeared in mainland France, carried by people travelling by airline. The French government of Dominique de Villepin sent an emergency aid package worth €36 million and deployed about 500 troops in an effort to eradicate mosquitoes on the island. [ citation needed ]Réunion sends seven deputies to the French National Assembly and three senators to the Senate . Réunion is an Overseas department and region of France (known in French as a Département et Région d'Outre-Mer , DROM) governed by Article 73 of the Constitution of France , under which the laws and regulations are applicable as of right, as in metropolitan France. Thus, Réunion has a regional council and a departmental council. These territorial entities have the same general powers as the departments and regions of metropolitan France, albeit with some adaptations. Article 73 of the Constitution provides for the possibility of replacing the region and the department by a single territorial entity, but, unlike French Guiana or Martinique , there are currently no plans to do so. Unlike the other DROMs, the Constitution explicitly excludes Réunion from the possibility of receiving authorization from Parliament to set certain rules itself, either by law or by the national executive. The State is represented in Réunion by a prefect . The territory is divided into four districts (Saint-Benoît, Saint-Denis, Saint-Paul and Saint-Pierre). Réunion has 24 municipalities organized into 5 agglomeration communities. From the point of view of the European Union , Réunion is considered an "outermost region." The positioning of Réunion Island has given it a more or less important strategic role depending on the period. Already at the time of the India Route or Route des Indes, Réunion was a French possession located between Cape Town and the Indian trading posts, although far from the Mozambique Channel . Île de Bourbon (its name under the Ancien Régime ) was not, however, the preferred position for trade and military. Governor Labourdonnais claimed that Île de France (Mauritius) was a land of opportunity, thanks to its topography and the presence of two natural harbours. He intended Île de Bourbon to be a depot or an emergency base for Île de France. The opening of the Suez Canal diverted much of the maritime traffic from the southern Indian Ocean and reduced the strategic importance of the island. This decline is confirmed by the importance given to Madagascar, which was later colonized. Today, the island, the seat of a defense and security zone, is the headquarters of the French Armed Forces of the Southern Indian Ocean Zone (FAZSOI), which brings together French Army units stationed in La Réunion and Mayotte. Réunion is also a base for the so-called Frenchelon signal intelligence system, whose infrastructure includes a mobile listening and automatic search unit. Saint-Pierre is also the headquarters of the mostly uninhabited French Southern and Antarctic Lands ( Terres australes et antarctiques françaises , TAAF). Because of France's possession of Réunion, France is a member of the Indian Ocean Commission , which also includes the Comoros , Madagascar , Mauritius and the Seychelles .Réunion is an Overseas department and region of France (known in French as a Département et Région d'Outre-Mer , DROM) governed by Article 73 of the Constitution of France , under which the laws and regulations are applicable as of right, as in metropolitan France. Thus, Réunion has a regional council and a departmental council. These territorial entities have the same general powers as the departments and regions of metropolitan France, albeit with some adaptations. Article 73 of the Constitution provides for the possibility of replacing the region and the department by a single territorial entity, but, unlike French Guiana or Martinique , there are currently no plans to do so. Unlike the other DROMs, the Constitution explicitly excludes Réunion from the possibility of receiving authorization from Parliament to set certain rules itself, either by law or by the national executive. The State is represented in Réunion by a prefect . The territory is divided into four districts (Saint-Benoît, Saint-Denis, Saint-Paul and Saint-Pierre). Réunion has 24 municipalities organized into 5 agglomeration communities. From the point of view of the European Union , Réunion is considered an "outermost region."The positioning of Réunion Island has given it a more or less important strategic role depending on the period. Already at the time of the India Route or Route des Indes, Réunion was a French possession located between Cape Town and the Indian trading posts, although far from the Mozambique Channel . Île de Bourbon (its name under the Ancien Régime ) was not, however, the preferred position for trade and military. Governor Labourdonnais claimed that Île de France (Mauritius) was a land of opportunity, thanks to its topography and the presence of two natural harbours. He intended Île de Bourbon to be a depot or an emergency base for Île de France. The opening of the Suez Canal diverted much of the maritime traffic from the southern Indian Ocean and reduced the strategic importance of the island. This decline is confirmed by the importance given to Madagascar, which was later colonized. Today, the island, the seat of a defense and security zone, is the headquarters of the French Armed Forces of the Southern Indian Ocean Zone (FAZSOI), which brings together French Army units stationed in La Réunion and Mayotte. Réunion is also a base for the so-called Frenchelon signal intelligence system, whose infrastructure includes a mobile listening and automatic search unit. Saint-Pierre is also the headquarters of the mostly uninhabited French Southern and Antarctic Lands ( Terres australes et antarctiques françaises , TAAF). Because of France's possession of Réunion, France is a member of the Indian Ocean Commission , which also includes the Comoros , Madagascar , Mauritius and the Seychelles .Administratively, Réunion is divided into 24 communes (municipalities) grouped into four arrondissements . It is also subdivided into 25 cantons , meaningful only for electoral purposes at the departmental or regional level. It is a French overseas department, hence a French overseas region. The low number of communes , compared with French metropolitan departments of similar size and population, is unique: most of its communes encompass several localities, sometimes separated by significant distances. The communes voluntarily grouped themselves into five groups for cooperating in some domains, apart from the four arrondissements to which they belong for purposes of national laws and executive regulation. After some changes in their composition, name and status, all of them operate with the status of agglomeration communities , and apply their own local taxation (in addition to national, regional, departmental, and municipal taxes) and have an autonomous budget decided by the assembly representing all member communes. This budget is also partly funded by the state, the region, the department, and the European Union for some development and investment programs. Every commune in Réunion is now a member of such an intercommunality, with its own taxation, to which member communes have delegated their authority in various areas.The communes voluntarily grouped themselves into five groups for cooperating in some domains, apart from the four arrondissements to which they belong for purposes of national laws and executive regulation. After some changes in their composition, name and status, all of them operate with the status of agglomeration communities , and apply their own local taxation (in addition to national, regional, departmental, and municipal taxes) and have an autonomous budget decided by the assembly representing all member communes. This budget is also partly funded by the state, the region, the department, and the European Union for some development and investment programs. Every commune in Réunion is now a member of such an intercommunality, with its own taxation, to which member communes have delegated their authority in various areas.Although diplomacy, military, and French government matters are handled by Paris, Réunion is a member of La Francophonie , the Indian Ocean Commission , the International Trade Union Confederation , the Universal Postal Union , the Port Management Association of Eastern and Southern Africa , and the World Federation of Trade Unions in its own right.The French Armed Forces are responsible for the defence of the department. These forces also contribute to the defence of other French territories in the region, including Mayotte and the French Southern and Antarctic Lands . A total of some 2,000 French troops are deployed in the region, mostly in Réunion centred on the 2nd Marine Infantry Parachute Regiment . Two CASA CN 235 aircraft, forming air detachment 181 and drawn from the 50th Air Transport squadron, provide a modest air transport and surveillance capability. In 2022, the French Air Force demonstrated a capacity to reinforce the territory by deploying two Rafale fighter aircraft, supported by an A330 MRTT Phénix tanker, from France to Réunion for a regional exercise. The French naval presence includes two Floréal -class frigates , Floréal and Nivôse , the icebreaker L'Astrolabe , the patrol and support ship Champlain and the coast guard vessel Le Malin . The naval aviation element includes Eurocopter AS565 Panther helicopters from Flottille 36F able to embark on the Floréal -class frigates as required. By 2025, Le Malin is to be replaced by Auguste Techer , a vessel of the new Félix Éboué class of patrol vessels. The French Navy will further reinforce its offshore patrol capabilities in the region by deploying a second vessel of the class ( Félix Éboué ) to Réunion by late 2025/early 2026. About 800 National Gendarmerie , including one mobile squadron and one high mountain platoon, are also stationed in Réunion. The Maritime Gendarmerie operates the patrol boat Verdon in the territory (though she was reported forward deployed in Mayotte as of 2022). The island is 63 km (39 mi) long; 45 km (28 mi) wide; and covers 2,512 km 2 (970 sq mi) . It is above a hotspot in the Earth's crust. The Piton de la Fournaise , a shield volcano on the eastern end of Réunion Island, rises more than 2,631 m (8,632 ft) above sea level and is sometimes called a sister to Hawaiian volcanoes because of the similarity of climate and volcanic nature. It has erupted more than 100 times since 1640, and is under constant monitoring, most recently erupting on 2 July 2023. During another eruption in April 2007, the lava flow was estimated at 3,000,000 m 3 (3,900,000 cu yd) per day. The hotspot that fuels Piton de la Fournaise also created the islands of Mauritius and Rodrigues . The Piton des Neiges volcano, the highest point on the island at 3,070 m (10,070 ft) above sea level, is northwest of the Piton de la Fournaise. Collapsed calderas and canyons are south west of the mountain. While the Piton de la Fournaise is one of Earth's most active volcanoes, the Piton des Neiges is dormant. Its name is French for "peak of snows", but snowfall on the summit of the mountain is rare. The slopes of both volcanoes are heavily forested. Cultivated land and cities like the capital city of Saint-Denis are concentrated on the surrounding coastal lowlands. Offshore, part of the west coast is characterised by a coral reef system . Réunion also has three calderas : the Cirque de Salazie , the Cirque de Cilaos and the Cirque de Mafate . The last is accessible only on foot or by helicopter. Réunion Island is a volcanic island born some three million years ago with the emergence of the Piton des Neiges volcano. It has an altitude of 3,070.5 m (10,074 ft) , the highest peak in the Mascarene Islands and the Indian Ocean. The eastern part of the island is constituted by the Piton de la Fournaise, a much more recent volcano (500,000 years old) which is considered one of the most active on the planet. The emerged part of the island represents only a small percentage (about 3%) of the underwater mountain that forms it. In addition to volcanism, the relief of the island is very uneven due to active erosion. The center shelters three vast cirques dug by erosion (Salazie, Mafate and Cilaos) and the slopes of the island are furrowed by numerous rivers digging gullies, estimated at least 600, generally deep and whose torrents cut the sides of the mountains up to several hundreds of meters deep. The ancient massif of the Piton des Neiges is separated from the massif of La Fournaise by a gap formed by the plaine des Palmistes and the plaine des Cafres, a passageway between the east and the south of the island. Apart from the plains, the coastal areas are generally the flattest regions, especially in the north and west of the island. The coastline of the wild south is however steeper. Between the coastal fringe and the Hauts, there is a steep transitional zone whose gradient varies considerably before arriving at the ridge lines setting the cirques or the Enclos, the caldera of the Piton de la Fournaise. The island of Réunion is characterized by a humid tropical climate , tempered by the oceanic influence of the trade winds blowing from east to west. The climate of Réunion is characterized by its great variability, mainly due to the imposing relief of the island, which is at the origin of numerous microclimates. As a result, there are strong disparities in rainfall between the windward coast in the east and the leeward coast in the west, and in temperature between the warmer coastal areas and the relatively cooler highland areas. In Réunion there are two distinct seasons, defined by the rainfall regime: a rainy season from January to March, during which most of the year's rain falls; a dry season from May to November. However, in the eastern part and in the foothills of the volcano , rainfall can be significant even in the dry season; April and December are transition months, sometimes very rainy but also very dry. Pointe des Trois Bassins, located on the coast of the commune of Trois-Bassins (west), is the driest season, with a normal annual precipitation of 447.7 mm (17.63 in) , while Le Baril, in Saint-Philippe (southeast), is the wettest coastal season, with a normal annual precipitation of 4,256.2 mm (167.57 in) . However, the wettest station is in the highlands of Sainte-Rose, with an average annual rainfall of almost 11,000 mm (430 in) , making it one of the wettest places in the world. Temperatures in Réunion are characterized by their great mildness throughout the year. In fact, the thermal amplitude from one season to another is relatively small (rarely exceeding 10 °C or 18 °F), although it is perceptible: In the warm season (November to April): average minimums usually range between 21 and 24 °C (70 and 75 °F) , and average maximums between 28 and 31 °C (82 and 88 °F) , on the coast. At 1,000 m (3,300 ft) , average minimums fluctuate between 10 and 14 °C (50 and 57 °F) and average maximums between 21 and 24 °C (70 and 75 °F) ; In the cold season (May to October): temperatures at sea level vary from 17 to 20 °C (63 to 68 °F) for average minimums and from 26 to 28 °C (79 to 82 °F) for average maximums. At 1,000 m (3,300 ft) , average minimums range from 8 to 10 °C (46 to 50 °F) and average maximums from 17 to 21 °C (63 to 70 °F) . In mountain towns, such as Cilaos or La Plaine-des-Palmistes, average temperatures range between 12 and 22 °C (54 and 72 °F) . The highest parts of the habitat and the natural areas at altitude may suffer some winter frosts. Snow was even observed on the Piton des Neiges and Piton de la Fournaise in 2003 and 2006. The warmest day on record set on 30 January 2022. In the cold pole of the Réunion Island (all-time low −5 °C or 23 °F ) Gite de Bellecombe ( 2,245 m or 7,365 ft AMSL ) with a maximum temperature of 25.4 °C (77.7 °F) on 30 January. It beats the previous record of 25.1 °C (77.2 °F) set in 2021 and 2021. While a growing number of islands (including "non-sovereign" islands) in the world are concerned about the effects of climate change, the island of Réunion was chosen (along with Gran Canaria in Spain) as an example for a case study of an affected ultra-European peripheral territory, for a study on the adequacy of urban and regional planning tools to the needs and characteristics of these islands (including land use and population density and the regulatory framework). This work confirmed that urban and peri-urban land use pressures are high, and that adaptation strategies are incompletely integrated into land use planning. According to the Institute of Island Studies, there is a dysfunction: "island planning tools often do not take climate change adaptation into account and there is too much top-down management in the decision-making process". Réunion holds the world records for the most rainfall in 12-, 24-, 72- and 96-hour periods, including 1.8 metres (5 ft 11 in) in 24 hours. Réunion hosts many tropical and unique beaches. They are often equipped with barbecues, amenities, and parking spaces. Hermitage Beach is the most extensive and best-preserved lagoon in Réunion Island and a popular snorkelling location. It is a white sand beach lined with casuarina trees under which the locals often organise picnics. La Plage des Brisants is a well-known surfing spot, with many athletic and leisurely activities taking place. Each November, a film festival is also organised in La Plage des Brisants. Movies are projected on a large screen in front of a crowd. Beaches at Boucan Canot are surrounded by a stretch of restaurants that particularly cater to tourists. L'Étang-Salé on the west coast is a particularly unique beach as it is covered in black sand consisting of tiny fragments of basalt. This occurs when lava contacts water, it cools rapidly and shatters into the sand and fragmented debris of various size. Much of the debris is small enough to be considered sand. Grand Anse is a tropical white-sand beach lined with coconut trees in the south of Réunion, with a rock pool built for swimmers, a pétanque playground, and a picnic area. Le Vieux Port in Saint Philippe is a green-sand beach consisting of tiny olivine crystals, formed by the 2007 lava flow, making it one of the youngest beaches on Earth. Réunion Island is a volcanic island born some three million years ago with the emergence of the Piton des Neiges volcano. It has an altitude of 3,070.5 m (10,074 ft) , the highest peak in the Mascarene Islands and the Indian Ocean. The eastern part of the island is constituted by the Piton de la Fournaise, a much more recent volcano (500,000 years old) which is considered one of the most active on the planet. The emerged part of the island represents only a small percentage (about 3%) of the underwater mountain that forms it. In addition to volcanism, the relief of the island is very uneven due to active erosion. The center shelters three vast cirques dug by erosion (Salazie, Mafate and Cilaos) and the slopes of the island are furrowed by numerous rivers digging gullies, estimated at least 600, generally deep and whose torrents cut the sides of the mountains up to several hundreds of meters deep. The ancient massif of the Piton des Neiges is separated from the massif of La Fournaise by a gap formed by the plaine des Palmistes and the plaine des Cafres, a passageway between the east and the south of the island. Apart from the plains, the coastal areas are generally the flattest regions, especially in the north and west of the island. The coastline of the wild south is however steeper. Between the coastal fringe and the Hauts, there is a steep transitional zone whose gradient varies considerably before arriving at the ridge lines setting the cirques or the Enclos, the caldera of the Piton de la Fournaise.The island of Réunion is characterized by a humid tropical climate , tempered by the oceanic influence of the trade winds blowing from east to west. The climate of Réunion is characterized by its great variability, mainly due to the imposing relief of the island, which is at the origin of numerous microclimates. As a result, there are strong disparities in rainfall between the windward coast in the east and the leeward coast in the west, and in temperature between the warmer coastal areas and the relatively cooler highland areas. In Réunion there are two distinct seasons, defined by the rainfall regime: a rainy season from January to March, during which most of the year's rain falls; a dry season from May to November. However, in the eastern part and in the foothills of the volcano , rainfall can be significant even in the dry season; April and December are transition months, sometimes very rainy but also very dry. Pointe des Trois Bassins, located on the coast of the commune of Trois-Bassins (west), is the driest season, with a normal annual precipitation of 447.7 mm (17.63 in) , while Le Baril, in Saint-Philippe (southeast), is the wettest coastal season, with a normal annual precipitation of 4,256.2 mm (167.57 in) . However, the wettest station is in the highlands of Sainte-Rose, with an average annual rainfall of almost 11,000 mm (430 in) , making it one of the wettest places in the world. Temperatures in Réunion are characterized by their great mildness throughout the year. In fact, the thermal amplitude from one season to another is relatively small (rarely exceeding 10 °C or 18 °F), although it is perceptible: In the warm season (November to April): average minimums usually range between 21 and 24 °C (70 and 75 °F) , and average maximums between 28 and 31 °C (82 and 88 °F) , on the coast. At 1,000 m (3,300 ft) , average minimums fluctuate between 10 and 14 °C (50 and 57 °F) and average maximums between 21 and 24 °C (70 and 75 °F) ; In the cold season (May to October): temperatures at sea level vary from 17 to 20 °C (63 to 68 °F) for average minimums and from 26 to 28 °C (79 to 82 °F) for average maximums. At 1,000 m (3,300 ft) , average minimums range from 8 to 10 °C (46 to 50 °F) and average maximums from 17 to 21 °C (63 to 70 °F) . In mountain towns, such as Cilaos or La Plaine-des-Palmistes, average temperatures range between 12 and 22 °C (54 and 72 °F) . The highest parts of the habitat and the natural areas at altitude may suffer some winter frosts. Snow was even observed on the Piton des Neiges and Piton de la Fournaise in 2003 and 2006. The warmest day on record set on 30 January 2022. In the cold pole of the Réunion Island (all-time low −5 °C or 23 °F ) Gite de Bellecombe ( 2,245 m or 7,365 ft AMSL ) with a maximum temperature of 25.4 °C (77.7 °F) on 30 January. It beats the previous record of 25.1 °C (77.2 °F) set in 2021 and 2021. While a growing number of islands (including "non-sovereign" islands) in the world are concerned about the effects of climate change, the island of Réunion was chosen (along with Gran Canaria in Spain) as an example for a case study of an affected ultra-European peripheral territory, for a study on the adequacy of urban and regional planning tools to the needs and characteristics of these islands (including land use and population density and the regulatory framework). This work confirmed that urban and peri-urban land use pressures are high, and that adaptation strategies are incompletely integrated into land use planning. According to the Institute of Island Studies, there is a dysfunction: "island planning tools often do not take climate change adaptation into account and there is too much top-down management in the decision-making process". Réunion holds the world records for the most rainfall in 12-, 24-, 72- and 96-hour periods, including 1.8 metres (5 ft 11 in) in 24 hours. Réunion hosts many tropical and unique beaches. They are often equipped with barbecues, amenities, and parking spaces. Hermitage Beach is the most extensive and best-preserved lagoon in Réunion Island and a popular snorkelling location. It is a white sand beach lined with casuarina trees under which the locals often organise picnics. La Plage des Brisants is a well-known surfing spot, with many athletic and leisurely activities taking place. Each November, a film festival is also organised in La Plage des Brisants. Movies are projected on a large screen in front of a crowd. Beaches at Boucan Canot are surrounded by a stretch of restaurants that particularly cater to tourists. L'Étang-Salé on the west coast is a particularly unique beach as it is covered in black sand consisting of tiny fragments of basalt. This occurs when lava contacts water, it cools rapidly and shatters into the sand and fragmented debris of various size. Much of the debris is small enough to be considered sand. Grand Anse is a tropical white-sand beach lined with coconut trees in the south of Réunion, with a rock pool built for swimmers, a pétanque playground, and a picnic area. Le Vieux Port in Saint Philippe is a green-sand beach consisting of tiny olivine crystals, formed by the 2007 lava flow, making it one of the youngest beaches on Earth. The tropical and insular flora of Réunion Island is characterized by its diversity, a very high rate of endemism and a very specific structure. The flora of Réunion presents a great diversity of natural environments and species (up to 40 tree species/ha, compared to a temperate forest which has an average of 5/ha). This diversity is even more remarkable, but fragile, as it differs according to the environment (coastal, low, medium and high mountain). Réunion has a very high rate of endemic species, with more than 850 native plants (of natural origin and present before the arrival of humans), of which 232 are endemic to the island of Réunion (only present on the island), as well as numerous species endemic to the Mascarene archipelago. Finally, the flora of Réunion is distinguished from that of equatorial tropical forests by the low height and density of the canopy, probably due to adaptation to cyclones, and by a very specific vegetation, in particular a strong presence of epiphytic plants (growing on other plants), such as orchids , bromeliads [ citation needed ] and cacti [ citation needed ] , but also ferns, lichens and mosses . Like its prodigious floral diversity, Réunion is home to a variety of birds such as the white-tailed tropicbird ( French: paille en queue ). Many of these birds species are endemic to the island, such as the Réunion harrier and Réunion cuckooshrike . Its largest land animal is the panther chameleon , Furcifer pardalis. Much of the west coast is ringed by coral reef which harbours, among other animals, sea urchins , conger eels , and parrot fish . Sea turtles and dolphins also inhabit the coastal waters. Humpback whales migrate north to the island from the Antarctic waters annually during the Southern Hemisphere winter (June–September) to breed and feed, and can be routinely observed from the shores of Réunion during this season. At least 19 species formerly endemic to Réunion have become extinct following human colonisation. For example, the Réunion giant tortoise became extinct after being slaughtered in vast numbers by sailors and settlers of the island. Despite the small area of coral reefs, the marine biodiversity of Réunion Island is comparable to that of other islands in the area, which has earned the Mascarene archipelago its inclusion among the top ten global biodiversity "hotspots". Réunion's coral reefs, both flat and barrier, are dominated mainly by fast-growing branching coral species of the genus Acropora (family Acroporidae), which provide shelter and food for many tropical species. Recent scientific research in Réunion Island indicates that there are more than 190 species of corals, more than 1,300 species of mollusks, more than 500 species of crustaceans, more than 130 species of echinoderms and more than 1,000 species of fish. Réunion's deeper waters are home to dolphins, killer whales, humpback whales, blue sharks and a variety of shark species, including whale sharks, coral sharks, bull sharks, tiger sharks, blacktip sharks and great white sharks. Several species of sea turtles live and breed here. Between 2010 and 2017, 23 shark attacks occurred in the waters of Réunion, of which nine were fatal. In July 2013, the Prefect of Réunion Michel Lalande announced a ban on swimming, surfing, and bodyboarding off more than half of the coast. Lalande also said 45 bull sharks and 45 tiger sharks would be culled , in addition to the 20 already killed as part of scientific research into the illness ciguatera . Migrations of humpback whales contributed to a boom of whale watching industries on Réunion, and watching rules have been governed by the OMAR (Observatoire Marin de la Réunion) and Globice (Groupe local d'observation et d'identification des cétacés) . Because the island is relatively young (3 million years old), the coral formations (8,000 years old) are not well developed and occupy a small area compared to older islands, mostly in the form of fringing reefs. These formations define shallow "lagoons" (rather "reef depressions"), the largest of which is no more than 200 m (660 ft) wide and about 1–2 m (3.3–6.6 ft) deep. These lagoons, which form a discontinuous reef belt 25 km (16 mi) long (i.e. 12% of the island's coastline) with a total area of 12 km 2 (4.6 sq mi) , are located on the west and southwest coast of the island. The most important are those of L'Ermitage (St-Gilles), St-Leu, L'Étang-Salé and St-Pierre. Since 2010, Réunion is home to a UNESCO World Heritage Site that covers about 40% of the island's area and coincides with the central zone of the Réunion National Park . The island is part of the Mascarene forests terrestrial ecoregion. The first members of the "Bourbon" group of garden roses originated on this island (then still Île Bourbon, hence the name) from a spontaneous hybridisation between Damask roses and Rosa chinensis , which had been brought there by the colonists. The first Bourbon roses were discovered on the island in 1817. Among coastal ecosystems , coral reefs are among the richest in biodiversity , but they are also the most fragile. Nearly one-third of fish species were already considered threatened or vulnerable in 2009, with coral degradation in many places. The causes of this state of affairs are pollution, overfishing and poaching, as well as anthropogenic pressure, especially linked to the densification of urbanization in coastal areas and the discharge of sewage. 15 species living on Réunion were included in the Red List published by the International Union for Conservation of Nature (IUCN). The tropical and insular flora of Réunion Island is characterized by its diversity, a very high rate of endemism and a very specific structure. The flora of Réunion presents a great diversity of natural environments and species (up to 40 tree species/ha, compared to a temperate forest which has an average of 5/ha). This diversity is even more remarkable, but fragile, as it differs according to the environment (coastal, low, medium and high mountain). Réunion has a very high rate of endemic species, with more than 850 native plants (of natural origin and present before the arrival of humans), of which 232 are endemic to the island of Réunion (only present on the island), as well as numerous species endemic to the Mascarene archipelago. Finally, the flora of Réunion is distinguished from that of equatorial tropical forests by the low height and density of the canopy, probably due to adaptation to cyclones, and by a very specific vegetation, in particular a strong presence of epiphytic plants (growing on other plants), such as orchids , bromeliads [ citation needed ] and cacti [ citation needed ] , but also ferns, lichens and mosses . Like its prodigious floral diversity, Réunion is home to a variety of birds such as the white-tailed tropicbird ( French: paille en queue ). Many of these birds species are endemic to the island, such as the Réunion harrier and Réunion cuckooshrike . Its largest land animal is the panther chameleon , Furcifer pardalis. Much of the west coast is ringed by coral reef which harbours, among other animals, sea urchins , conger eels , and parrot fish . Sea turtles and dolphins also inhabit the coastal waters. Humpback whales migrate north to the island from the Antarctic waters annually during the Southern Hemisphere winter (June–September) to breed and feed, and can be routinely observed from the shores of Réunion during this season. At least 19 species formerly endemic to Réunion have become extinct following human colonisation. For example, the Réunion giant tortoise became extinct after being slaughtered in vast numbers by sailors and settlers of the island.Despite the small area of coral reefs, the marine biodiversity of Réunion Island is comparable to that of other islands in the area, which has earned the Mascarene archipelago its inclusion among the top ten global biodiversity "hotspots". Réunion's coral reefs, both flat and barrier, are dominated mainly by fast-growing branching coral species of the genus Acropora (family Acroporidae), which provide shelter and food for many tropical species. Recent scientific research in Réunion Island indicates that there are more than 190 species of corals, more than 1,300 species of mollusks, more than 500 species of crustaceans, more than 130 species of echinoderms and more than 1,000 species of fish. Réunion's deeper waters are home to dolphins, killer whales, humpback whales, blue sharks and a variety of shark species, including whale sharks, coral sharks, bull sharks, tiger sharks, blacktip sharks and great white sharks. Several species of sea turtles live and breed here. Between 2010 and 2017, 23 shark attacks occurred in the waters of Réunion, of which nine were fatal. In July 2013, the Prefect of Réunion Michel Lalande announced a ban on swimming, surfing, and bodyboarding off more than half of the coast. Lalande also said 45 bull sharks and 45 tiger sharks would be culled , in addition to the 20 already killed as part of scientific research into the illness ciguatera . Migrations of humpback whales contributed to a boom of whale watching industries on Réunion, and watching rules have been governed by the OMAR (Observatoire Marin de la Réunion) and Globice (Groupe local d'observation et d'identification des cétacés) .Because the island is relatively young (3 million years old), the coral formations (8,000 years old) are not well developed and occupy a small area compared to older islands, mostly in the form of fringing reefs. These formations define shallow "lagoons" (rather "reef depressions"), the largest of which is no more than 200 m (660 ft) wide and about 1–2 m (3.3–6.6 ft) deep. These lagoons, which form a discontinuous reef belt 25 km (16 mi) long (i.e. 12% of the island's coastline) with a total area of 12 km 2 (4.6 sq mi) , are located on the west and southwest coast of the island. The most important are those of L'Ermitage (St-Gilles), St-Leu, L'Étang-Salé and St-Pierre.Since 2010, Réunion is home to a UNESCO World Heritage Site that covers about 40% of the island's area and coincides with the central zone of the Réunion National Park . The island is part of the Mascarene forests terrestrial ecoregion. The first members of the "Bourbon" group of garden roses originated on this island (then still Île Bourbon, hence the name) from a spontaneous hybridisation between Damask roses and Rosa chinensis , which had been brought there by the colonists. The first Bourbon roses were discovered on the island in 1817. The first members of the "Bourbon" group of garden roses originated on this island (then still Île Bourbon, hence the name) from a spontaneous hybridisation between Damask roses and Rosa chinensis , which had been brought there by the colonists. The first Bourbon roses were discovered on the island in 1817. Among coastal ecosystems , coral reefs are among the richest in biodiversity , but they are also the most fragile. Nearly one-third of fish species were already considered threatened or vulnerable in 2009, with coral degradation in many places. The causes of this state of affairs are pollution, overfishing and poaching, as well as anthropogenic pressure, especially linked to the densification of urbanization in coastal areas and the discharge of sewage. 15 species living on Réunion were included in the Red List published by the International Union for Conservation of Nature (IUCN). The most populous metropolitan area is Saint-Denis , which covers 6 communes (Saint-Denis, Sainte-Marie , La Possession , Sainte-Suzanne , Saint-André , and Bras-Panon ) in the north of the island. The three largest metropolitan areas are: At the 2019 census, 82.4% of the inhabitants of Réunion were born on the island, 11.7% were born in Metropolitan France , 1.0% were born in Mayotte , 0.3% were born in the rest of Overseas France , and 4.6% were born in foreign countries (46% of them children of French expatriates and settlers born in foreign countries, such as children of Réunionese settlers born in Madagascar during colonial times; the other 54% immigrants, i.e. people born in foreign countries with no French nationality at birth). In recent decades, the number of Metropolitan Frenchmen living on the island of Réunion has increased markedly: only 5,664 natives of Metropolitan France lived in Réunion at the 1967 census, but their numbers were multiplied by more than 6 in 23 years, reaching 37,516 at the 1990 census, and then nearly tripled in the next 29 years, reaching 100,493 at the 2019 census. Native Réunionese, meanwhile, have emigrated increasingly to Metropolitan France: the number of natives of Réunion living in Metropolitan France rose from 16,548 at the 1968 census to 92,354 at the 1990 census to 130,662 at the 2019 census, by which date 15.7% of the natives of Réunion lived outside of Réunion. Réunion has experienced extremely little immigration of foreigners since World War Two, and by the 2019 census only 2.5% of the inhabitants of Réunion were immigrants. This is in contrast to the situation that prevailed from the middle of the 19th century until World War Two when many migrants from India (especially from Tamil Nadu and Gujarat ), Eastern Asia (particularly China), and Africa came to Réunion to work in the plantation economy. Their descendants have now become French citizens. Ethnic groups present include people of African , Indian , European , Malagasy and Chinese origin. Local names for these are Yabs, Cafres , Malbars and Chinois . All of the ethnic groups on the island are immigrant populations that have come to Réunion from Europe, Asia and Africa over the centuries. There are no indigenous people on the island, as it was originally deserted. These populations have mixed from the earliest days of the island's colonial history (the first settlers married women from Madagascar and of Indo-Portuguese heritage), resulting in a majority population of mixed race and of "Creole" culture. It is not known exactly how many people of each ethnicity live in Réunion, since the French census does not ask questions about ethnic origin, which applies in Réunion because it is a part of France in accordance with the 1958 constitution . The extent of racial mixing on the island also makes ethnic estimates difficult. According to estimates, Whites make up roughly one quarter of the population, Malbars make up more than 25% of the population and people of Chinese ancestry form roughly 3%. The percentages for those of African and mixed-race origins vary widely in estimates. Also, some people of Vietnamese ancestry live on the island, though they are very few in number. Tamils are the largest group among the Indian community. The island's community of Muslims from northwestern India, particularly Gujarat , and elsewhere is commonly referred to as zarabes . Creoles (a name given to those born on the island, regardless of ethnic origins) make up the majority of the population. Groups that are not Creole include people recently arrived from Metropolitan France (known as zoreilles ) and those from Mayotte and the Comoros as well as immigrants from Madagascar and Sri Lankan Tamil refugees. Religious affiliation (2000 censuses) The predominant religion is Christianity. The Catholic Church has a single jurisdiction, the Diocese of Saint-Denis-de-La Réunion . Religious Intelligence estimates Christians to be 84.9% of the population, followed by Hindus (10%) and Muslims (2.15%). Chinese folk religion and Buddhism are also represented, among others. Most large towns have a Hindu temple and a mosque. The most populous metropolitan area is Saint-Denis , which covers 6 communes (Saint-Denis, Sainte-Marie , La Possession , Sainte-Suzanne , Saint-André , and Bras-Panon ) in the north of the island. The three largest metropolitan areas are: At the 2019 census, 82.4% of the inhabitants of Réunion were born on the island, 11.7% were born in Metropolitan France , 1.0% were born in Mayotte , 0.3% were born in the rest of Overseas France , and 4.6% were born in foreign countries (46% of them children of French expatriates and settlers born in foreign countries, such as children of Réunionese settlers born in Madagascar during colonial times; the other 54% immigrants, i.e. people born in foreign countries with no French nationality at birth). In recent decades, the number of Metropolitan Frenchmen living on the island of Réunion has increased markedly: only 5,664 natives of Metropolitan France lived in Réunion at the 1967 census, but their numbers were multiplied by more than 6 in 23 years, reaching 37,516 at the 1990 census, and then nearly tripled in the next 29 years, reaching 100,493 at the 2019 census. Native Réunionese, meanwhile, have emigrated increasingly to Metropolitan France: the number of natives of Réunion living in Metropolitan France rose from 16,548 at the 1968 census to 92,354 at the 1990 census to 130,662 at the 2019 census, by which date 15.7% of the natives of Réunion lived outside of Réunion. Réunion has experienced extremely little immigration of foreigners since World War Two, and by the 2019 census only 2.5% of the inhabitants of Réunion were immigrants. This is in contrast to the situation that prevailed from the middle of the 19th century until World War Two when many migrants from India (especially from Tamil Nadu and Gujarat ), Eastern Asia (particularly China), and Africa came to Réunion to work in the plantation economy. Their descendants have now become French citizens. Ethnic groups present include people of African , Indian , European , Malagasy and Chinese origin. Local names for these are Yabs, Cafres , Malbars and Chinois . All of the ethnic groups on the island are immigrant populations that have come to Réunion from Europe, Asia and Africa over the centuries. There are no indigenous people on the island, as it was originally deserted. These populations have mixed from the earliest days of the island's colonial history (the first settlers married women from Madagascar and of Indo-Portuguese heritage), resulting in a majority population of mixed race and of "Creole" culture. It is not known exactly how many people of each ethnicity live in Réunion, since the French census does not ask questions about ethnic origin, which applies in Réunion because it is a part of France in accordance with the 1958 constitution . The extent of racial mixing on the island also makes ethnic estimates difficult. According to estimates, Whites make up roughly one quarter of the population, Malbars make up more than 25% of the population and people of Chinese ancestry form roughly 3%. The percentages for those of African and mixed-race origins vary widely in estimates. Also, some people of Vietnamese ancestry live on the island, though they are very few in number. Tamils are the largest group among the Indian community. The island's community of Muslims from northwestern India, particularly Gujarat , and elsewhere is commonly referred to as zarabes . Creoles (a name given to those born on the island, regardless of ethnic origins) make up the majority of the population. Groups that are not Creole include people recently arrived from Metropolitan France (known as zoreilles ) and those from Mayotte and the Comoros as well as immigrants from Madagascar and Sri Lankan Tamil refugees.Religious affiliation (2000 censuses) The predominant religion is Christianity. The Catholic Church has a single jurisdiction, the Diocese of Saint-Denis-de-La Réunion . Religious Intelligence estimates Christians to be 84.9% of the population, followed by Hindus (10%) and Muslims (2.15%). Chinese folk religion and Buddhism are also represented, among others. Most large towns have a Hindu temple and a mosque. Réunionese culture is a blend ( métissage ) of European, African, Indian , Chinese and insular traditions. The most widely spoken language, Réunion Creole , derives from French . French is the sole official language of Réunion. Though not official, Réunion Creole is widely spoken alongside French. Creole is commonly used for informal purposes, whereas the official language for administrative purposes, as well as education, is French. Other languages spoken on Réunion include: Comorian varieties (especially Shimaore ) and Malagasy , by recent immigrants from Mayotte and Madagascar; Mandarin , Hakka and Cantonese by members of the Chinese community; Indian languages , mostly Tamil , Gujarati and Hindi ; and Arabic , spoken by a small community of Muslims. These languages are generally spoken by immigrants, as those born on the island tend to use French and Creole. Cantonese , Arabic and Tamil are offered as optional languages in some schools. There are two music genres which originated in Réunion: sega, which originated earlier and is also traditional in Mauritius, Rodrigues and Seychelles, and maloya, which originated in the 19th century and is only found in Réunion. Every 20 December, the inhabitants of Réunion Island celebrate Réunion Freedom Day. This celebration, also known as the Fête des Cafres or "Fet' Kaf'", commemorates the proclamation of the abolition of slavery by the Second Republic (France) in 1848. The term "cafre" refers to the Africans of the "Cafrerie" (a part of southern Africa). It derives from the Afrikaans word "kaffer", which is similar to the American slang " nigger " or "nègre", originating in colonial France. Today, in the 21st century, Reunionese celebrate with joy the end of a long period of oppression. Cafres, Malagasy, Comorians, Indians, Yabs, Z'oreilles and metropolitans gather in the streets dancing to the rhythm of the sega and the maloya, the two great musical genres of Réunion. Numerous concerts are organized, most of them free, as well as costume parades and dance shows such as merengue , for example. Always accompanied by rice, the most common dishes are carry (sometimes spelled cari), a local version of Indian curry , rougail and civets (stews). Curry is made with a base of onion, garlic and spices such as turmeric (called "safran péi" on the island), on which fish, meat and eggs are fried; tomato is then added. Dishes can also be flavoured with ginger; the peel of a combava is often prized. Chop suey (with rice, not pasta) and other Asian dishes such as pork with pineapple Some examples of popular réunionese dishes include: Achards (inspired by achaar ) Cabri massalé Cari poulet Rougail dakatine Rougail morue Rougail saucisse Bouchon In general, there are few dishes without meat or fish, so there are few vegetarian options . One of them is chouchou chayote gratin. Otherwise, mainly poultry is consumed. One of the local specialties is tangue civet (of the hedgehog family). Moringue is a popular combat/dance sport similar to capoeira . There are several famous Réunionese sportsmen and women like the handballer Jackson Richardson , as well as the karateka Lucie Ignace . Réunion has a number of contributions to worldwide professional surfing . It has been home to notable pro surfers including Jeremy Flores , Johanne Defay and Justine Mauvin . Famous break St Leu has been host to several world surfing championship competitions. Since 1992, Réunion has hosted a number of ultramarathons under the umbrella name of the Grand Raid . As of 2018, four different races compose the Grand Raid: the Diagonale des Fous, The Trail de Bourbon, the Mascareignes, and the Zembrocal Trail. Annual athletics Meeting de la Réunion is held at the Stade Paul Julius Bénard by the governing body Ligue Réunionnaise d'athlétisme . Football is the most popular sport. With more than 30,000 licensed players for a population exceeding 850,000 inhabitants, it remains the sport of choice for young people. Although the highest level of competition called the First Division of Réunion is equivalent to a division d'honneur in metropolitan France (DH), all the youngsters hope to play at the highest level one day. This has been the case for players such as Laurent Robert , Florent Sinama-Pongolle , Guillaume Hoarau , Dimitri Payet , Benoit Tremoulinas (the only five Reunionese to have played for the French national team), Bertrand Robert , Thomas Fontaine , Ludovic Ajorque , Fabrice Abriel (of Réunion descent) and Wilfried Moimbe (of Réunion descent), to name but a few. The territory has its own team, the Réunion national football team . Structurally, the local Creole house is said to be symmetrical. In fact, in the absence of an architect, workers would draw a line on the ground and build two identical parts on each side, resulting in houses of essentially rectangular shape. The veranda is an important element of the house. It is an outdoor terrace built on the front of the house, as it allowed to show its richness to the street. A Creole garden completes the house. It is composed of local plants, found in the forest. There is usually a greenhouse with orchids, anthuriums and different types of ferns. The Villa Déramond-Barre is a Creole architectural model of great heritage interest. Two forms of musical expression historically make up the folkloric tradition of Réunion Island. One, the sega, is a Creole variant of the quadrille , the other, the maloya, like the American blues, comes from Africa, carried by the nostalgia and pain of slaves uprooted and deported from their homeland. The sega, a disguised ballroom dance to the rhythm of traditional Western instruments (accordion, harmonica, guitar, etc.), is a testament to the fun of colonial society at the time. Today, it is still the typical ballroom dance of the island of Réunion and the Mascarene archipelago in general, along with the Mauritian sega and the Rhodesian sega. The slaves' maloya, a ritual dance full of melodies and gestures, was performed almost clandestinely at night around a bonfire; the few instruments that accompanied it were made of plants (bamboo, gourds, etc.). Beyond their taste for this musical art form, the maloya troupes wanted to perpetuate the memory of the slaves , their suffering and their uprooting. Through sometimes controversial texts, they remind France of its slave-owning past and underline the damage that this colonial era did to human beings; in the course of the island's history, maloya artists and kabars (gatherings) were sometimes banned by the authorities. With the institution of a public holiday to celebrate the abolition of slavery (fête caf', 20 December), maloya has received official recognition; it is regularly played on public radio and many discotheques and dance parties programme it regularly; it is even enjoying a revival: groups have begun to make modern versions, styles and arrangements, such as maloggae and other electric maloya. Some of Réunion Island's emblematic musical groups include: Groupe folklorique de La Réunion, Kalou Pilé, Baster, Ousanousava, Ziskakan, Pat'Jaune, Danyèl Waro , Tisours, etc. We can also mention one of the greatest Maloya singers: Lo Rwa Kaf. Born in Sainte-Suzanne, he was one of the first to sing Maloya. When he died in 2004, many people were present at his funeral. In 2008, the artist Brice Guilbert made a video clip entitled La Réunion. In this clip, we see him crossing all the landscapes of the island. In the field of contemporary dance, we can mention the choreographer Pascal Montrouge, who directs the only company in France that has a double headquarters in Saint-Denis de La Réunion and Hyères, which reinforces the sense of his vision of identity. In 2007, the city of Saint-Denis de La Réunion entrusted him with the artistic direction of its Saint-Denis Danses festival. The island is home to the regional conservatory of La Réunion, which has four teaching centres and was created in 1987 under the impetus of the then president of the region, Pierre Lagourgue. Today, although traditional dances are not forgotten in the conservatoires (which teach dance, music and theatre), the dances taught are classical dance, contemporary dance and Bharata natyam dance. These students regularly have the opportunity to dance with choreographers from Réunion such as Didier Boutiana cie "Konpani Soul city", Soraya Thomas cie "Morphose" or Éric Languet cie "Danse en l'R". These different local companies allow the inhabitants of Réunion to dance professionally. Urban culture has also made its appearance, following the trends and influences of metropolitan France and the United States. Thus, hip-hop culture is developing, but also ragga dancehall, with KM David or Kaf Malbar being the figurehead of this new movement, influencing the young generation all over the island, with their songs spread by mp3 or internet. Many young artists are trying to "break through" in this music, whose industry is developing reasonably well, locally but also internationally, and has nothing to envy from the precursors of French dancehall .French is the sole official language of Réunion. Though not official, Réunion Creole is widely spoken alongside French. Creole is commonly used for informal purposes, whereas the official language for administrative purposes, as well as education, is French. Other languages spoken on Réunion include: Comorian varieties (especially Shimaore ) and Malagasy , by recent immigrants from Mayotte and Madagascar; Mandarin , Hakka and Cantonese by members of the Chinese community; Indian languages , mostly Tamil , Gujarati and Hindi ; and Arabic , spoken by a small community of Muslims. These languages are generally spoken by immigrants, as those born on the island tend to use French and Creole. Cantonese , Arabic and Tamil are offered as optional languages in some schools. There are two music genres which originated in Réunion: sega, which originated earlier and is also traditional in Mauritius, Rodrigues and Seychelles, and maloya, which originated in the 19th century and is only found in Réunion. Every 20 December, the inhabitants of Réunion Island celebrate Réunion Freedom Day. This celebration, also known as the Fête des Cafres or "Fet' Kaf'", commemorates the proclamation of the abolition of slavery by the Second Republic (France) in 1848. The term "cafre" refers to the Africans of the "Cafrerie" (a part of southern Africa). It derives from the Afrikaans word "kaffer", which is similar to the American slang " nigger " or "nègre", originating in colonial France. Today, in the 21st century, Reunionese celebrate with joy the end of a long period of oppression. Cafres, Malagasy, Comorians, Indians, Yabs, Z'oreilles and metropolitans gather in the streets dancing to the rhythm of the sega and the maloya, the two great musical genres of Réunion. Numerous concerts are organized, most of them free, as well as costume parades and dance shows such as merengue , for example.Always accompanied by rice, the most common dishes are carry (sometimes spelled cari), a local version of Indian curry , rougail and civets (stews). Curry is made with a base of onion, garlic and spices such as turmeric (called "safran péi" on the island), on which fish, meat and eggs are fried; tomato is then added. Dishes can also be flavoured with ginger; the peel of a combava is often prized. Chop suey (with rice, not pasta) and other Asian dishes such as pork with pineapple Some examples of popular réunionese dishes include: Achards (inspired by achaar ) Cabri massalé Cari poulet Rougail dakatine Rougail morue Rougail saucisse Bouchon In general, there are few dishes without meat or fish, so there are few vegetarian options . One of them is chouchou chayote gratin. Otherwise, mainly poultry is consumed. One of the local specialties is tangue civet (of the hedgehog family).Moringue is a popular combat/dance sport similar to capoeira . There are several famous Réunionese sportsmen and women like the handballer Jackson Richardson , as well as the karateka Lucie Ignace . Réunion has a number of contributions to worldwide professional surfing . It has been home to notable pro surfers including Jeremy Flores , Johanne Defay and Justine Mauvin . Famous break St Leu has been host to several world surfing championship competitions. Since 1992, Réunion has hosted a number of ultramarathons under the umbrella name of the Grand Raid . As of 2018, four different races compose the Grand Raid: the Diagonale des Fous, The Trail de Bourbon, the Mascareignes, and the Zembrocal Trail. Annual athletics Meeting de la Réunion is held at the Stade Paul Julius Bénard by the governing body Ligue Réunionnaise d'athlétisme . Football is the most popular sport. With more than 30,000 licensed players for a population exceeding 850,000 inhabitants, it remains the sport of choice for young people. Although the highest level of competition called the First Division of Réunion is equivalent to a division d'honneur in metropolitan France (DH), all the youngsters hope to play at the highest level one day. This has been the case for players such as Laurent Robert , Florent Sinama-Pongolle , Guillaume Hoarau , Dimitri Payet , Benoit Tremoulinas (the only five Reunionese to have played for the French national team), Bertrand Robert , Thomas Fontaine , Ludovic Ajorque , Fabrice Abriel (of Réunion descent) and Wilfried Moimbe (of Réunion descent), to name but a few. The territory has its own team, the Réunion national football team .Football is the most popular sport. With more than 30,000 licensed players for a population exceeding 850,000 inhabitants, it remains the sport of choice for young people. Although the highest level of competition called the First Division of Réunion is equivalent to a division d'honneur in metropolitan France (DH), all the youngsters hope to play at the highest level one day. This has been the case for players such as Laurent Robert , Florent Sinama-Pongolle , Guillaume Hoarau , Dimitri Payet , Benoit Tremoulinas (the only five Reunionese to have played for the French national team), Bertrand Robert , Thomas Fontaine , Ludovic Ajorque , Fabrice Abriel (of Réunion descent) and Wilfried Moimbe (of Réunion descent), to name but a few. The territory has its own team, the Réunion national football team .Structurally, the local Creole house is said to be symmetrical. In fact, in the absence of an architect, workers would draw a line on the ground and build two identical parts on each side, resulting in houses of essentially rectangular shape. The veranda is an important element of the house. It is an outdoor terrace built on the front of the house, as it allowed to show its richness to the street. A Creole garden completes the house. It is composed of local plants, found in the forest. There is usually a greenhouse with orchids, anthuriums and different types of ferns. The Villa Déramond-Barre is a Creole architectural model of great heritage interest. Two forms of musical expression historically make up the folkloric tradition of Réunion Island. One, the sega, is a Creole variant of the quadrille , the other, the maloya, like the American blues, comes from Africa, carried by the nostalgia and pain of slaves uprooted and deported from their homeland. The sega, a disguised ballroom dance to the rhythm of traditional Western instruments (accordion, harmonica, guitar, etc.), is a testament to the fun of colonial society at the time. Today, it is still the typical ballroom dance of the island of Réunion and the Mascarene archipelago in general, along with the Mauritian sega and the Rhodesian sega. The slaves' maloya, a ritual dance full of melodies and gestures, was performed almost clandestinely at night around a bonfire; the few instruments that accompanied it were made of plants (bamboo, gourds, etc.). Beyond their taste for this musical art form, the maloya troupes wanted to perpetuate the memory of the slaves , their suffering and their uprooting. Through sometimes controversial texts, they remind France of its slave-owning past and underline the damage that this colonial era did to human beings; in the course of the island's history, maloya artists and kabars (gatherings) were sometimes banned by the authorities. With the institution of a public holiday to celebrate the abolition of slavery (fête caf', 20 December), maloya has received official recognition; it is regularly played on public radio and many discotheques and dance parties programme it regularly; it is even enjoying a revival: groups have begun to make modern versions, styles and arrangements, such as maloggae and other electric maloya. Some of Réunion Island's emblematic musical groups include: Groupe folklorique de La Réunion, Kalou Pilé, Baster, Ousanousava, Ziskakan, Pat'Jaune, Danyèl Waro , Tisours, etc. We can also mention one of the greatest Maloya singers: Lo Rwa Kaf. Born in Sainte-Suzanne, he was one of the first to sing Maloya. When he died in 2004, many people were present at his funeral. In 2008, the artist Brice Guilbert made a video clip entitled La Réunion. In this clip, we see him crossing all the landscapes of the island. In the field of contemporary dance, we can mention the choreographer Pascal Montrouge, who directs the only company in France that has a double headquarters in Saint-Denis de La Réunion and Hyères, which reinforces the sense of his vision of identity. In 2007, the city of Saint-Denis de La Réunion entrusted him with the artistic direction of its Saint-Denis Danses festival. The island is home to the regional conservatory of La Réunion, which has four teaching centres and was created in 1987 under the impetus of the then president of the region, Pierre Lagourgue. Today, although traditional dances are not forgotten in the conservatoires (which teach dance, music and theatre), the dances taught are classical dance, contemporary dance and Bharata natyam dance. These students regularly have the opportunity to dance with choreographers from Réunion such as Didier Boutiana cie "Konpani Soul city", Soraya Thomas cie "Morphose" or Éric Languet cie "Danse en l'R". These different local companies allow the inhabitants of Réunion to dance professionally. Urban culture has also made its appearance, following the trends and influences of metropolitan France and the United States. Thus, hip-hop culture is developing, but also ragga dancehall, with KM David or Kaf Malbar being the figurehead of this new movement, influencing the young generation all over the island, with their songs spread by mp3 or internet. Many young artists are trying to "break through" in this music, whose industry is developing reasonably well, locally but also internationally, and has nothing to envy from the precursors of French dancehall .Réunion has a local public television channel, Réunion 1ère , which now forms part of France Télévision , and also receives France 2 , France 3 , France 4 , France 5 and France 24 from metropolitan France, as well as France Ô , which shows programming from all of the overseas departments and territories . There are also two local private channels, Télé Kréol and Antenne Réunion. It has a local public radio station, formerly Radio Réunion, but now known as Réunion 1ère, like its television counterpart. It also receives the Radio France networks France Inter , France Musique and France Culture . The first private local radio station, Radio Freedom, was introduced in 1981. They broadcast daily content about weather and local services. Two main newspapers: Present on the island since 1896, is marked by its insularity and its geographical distance from metropolitan France . In the absence of the Centre national de la cinématographie (CNC), it has developed specific distribution and dissemination networks. Its landscapes first served as a natural backdrop for many film and television productions, and film events, such as festivals, multiplied there. Digital technology now facilitates the development of local productions, most of which reflect the particularities of a multicultural and multilingual society. The Réunion Film festival (festival du film de La Réunion) was created in 2005 and is chaired by Fabienne Redt. The festival presented first and second feature films by French directors. The 10th and last edition took place in 2014 in partnership mainly with the TEAT Champ Fleuri (Saint-Denis) and the city of Saint-Paul. In the Port, the International Film Festival of Africa and the Réunion Islands (Festival international du film d'Afrique et des îles de La Réunion) was also held. Among the existing film festivals is the Réunion Island Adventure Film Festival (13 editions), which awards prizes to adventure films. In Saint-Philippe, the Festival Même pas peur, Réunion's international fantasy film festival, has been held since 2010. In Saint-Pierre, there are two festivals: Écran jeunes (25th edition in 2019) and the Festival du Film Court de Saint-Pierre, directed by Armand Dauphin (3rd edition in 2019). The Internet situation in Réunion was once marked by its insularity and remoteness from mainland France, which caused some technological delays. Today, the trend has been reversed and the region has a relatively efficient Internet connection and is one of the departments most connected by fibre optics in France. Internet connection can be provided by ADSL (offered by four operators), fibre optic (three operators), or by cellular data on 4G and 5G networks (currently being tested in Saint-Denis). Réunion domain names have the suffix .re . The Réunion region has deployed a regional fibre-optic network for operators. This network is based partly on EDF's very high voltage cables - G@zelle network, partly on the region's own fibre and partly on Hertzian links for the most isolated areas. This network is managed by a public service company called La Réunion Numérique. Réunion has a local public television channel, Réunion 1ère , which now forms part of France Télévision , and also receives France 2 , France 3 , France 4 , France 5 and France 24 from metropolitan France, as well as France Ô , which shows programming from all of the overseas departments and territories . There are also two local private channels, Télé Kréol and Antenne Réunion. It has a local public radio station, formerly Radio Réunion, but now known as Réunion 1ère, like its television counterpart. It also receives the Radio France networks France Inter , France Musique and France Culture . The first private local radio station, Radio Freedom, was introduced in 1981. They broadcast daily content about weather and local services.Two main newspapers:Present on the island since 1896, is marked by its insularity and its geographical distance from metropolitan France . In the absence of the Centre national de la cinématographie (CNC), it has developed specific distribution and dissemination networks. Its landscapes first served as a natural backdrop for many film and television productions, and film events, such as festivals, multiplied there. Digital technology now facilitates the development of local productions, most of which reflect the particularities of a multicultural and multilingual society. The Réunion Film festival (festival du film de La Réunion) was created in 2005 and is chaired by Fabienne Redt. The festival presented first and second feature films by French directors. The 10th and last edition took place in 2014 in partnership mainly with the TEAT Champ Fleuri (Saint-Denis) and the city of Saint-Paul. In the Port, the International Film Festival of Africa and the Réunion Islands (Festival international du film d'Afrique et des îles de La Réunion) was also held. Among the existing film festivals is the Réunion Island Adventure Film Festival (13 editions), which awards prizes to adventure films. In Saint-Philippe, the Festival Même pas peur, Réunion's international fantasy film festival, has been held since 2010. In Saint-Pierre, there are two festivals: Écran jeunes (25th edition in 2019) and the Festival du Film Court de Saint-Pierre, directed by Armand Dauphin (3rd edition in 2019).The Internet situation in Réunion was once marked by its insularity and remoteness from mainland France, which caused some technological delays. Today, the trend has been reversed and the region has a relatively efficient Internet connection and is one of the departments most connected by fibre optics in France. Internet connection can be provided by ADSL (offered by four operators), fibre optic (three operators), or by cellular data on 4G and 5G networks (currently being tested in Saint-Denis). Réunion domain names have the suffix .re . The Réunion region has deployed a regional fibre-optic network for operators. This network is based partly on EDF's very high voltage cables - G@zelle network, partly on the region's own fibre and partly on Hertzian links for the most isolated areas. This network is managed by a public service company called La Réunion Numérique. In 2019, the GDP of Réunion at market exchange rates, not at PPP , was estimated at 19.5 billion euros (US$21.8 bn) and the GDP per capita (also at market exchange rates) was 22,629 euros (US$25,333), [ citation needed ] the highest in sub-Saharan Africa, but only 61.7% of metropolitan France 's GDP per capita that year, and 73.5% of the metropolitan French regions outside the Paris Region . Before the Global Financial Crisis of 2008 , the economy of Réunion was in a process of catching up with the rest of France. From 1997 to 2007, the economy of Réunion grew by an average of +4.6% per year in real terms , and the GDP per capita rose from 53.7% of metropolitan France's level in 2000 to 61.6% of metropolitan France in 2007. The Great Recession that followed the financial crisis greatly affected Réunion whose economy came to a standstill in 2008, then experienced two years of recession in 2009 and 2010, followed by three years of stagnation (2011-2013). By 2013, the GDP per capita of Réunion had fallen back to 60.6% of metropolitan France's level. Economic growth returned in 2014. The economy grew by an average of +2.9% per year in real terms from 2014 to 2017, and the GDP per capita of Réunion rose to 62.4% of metropolitan France's GDP per capita by 2017, its highest level ever. The economy slowed down in 2018, growing at only +1.7% due in part to the yellow vests protests which paralyzed the Réunionese economy in the end of 2018, before recovering to +2.2% in 2019. As a result of this slower growth since 2018, the GDP per capita of Réunion fell back slightly compared to metropolitan France's, standing at 61.7% of metropolitan France's level in 2019. Réunion was affected by the COVID-19 pandemic in 2020, leading to a massive recession of -4.2% that year according to provisional estimates, the largest on record, although less severe than in metropolitan France (-7.9% for metropolitan France in 2020). Sugar was traditionally the chief agricultural product and export. Tourism is now an important source of income. The island's remote location combined with its stable political alignment with Europe makes it a key location for satellite receiving stations and naval navigation. GDP sector composition in 2017 (contribution of each sector to the total gross value added ): Unemployment is a major problem on Réunion, although the situation has improved markedly since the beginning of the 2000s: the unemployment rate, which stood above 30% from the early 1980s to the early 2000s, declined to 24.6% in 2007, then rebounded to 30.0% in 2011 due to the 2008 global financial crisis and subsequent Great Recession , but declined again after 2011, reaching 21.5% in 2019, its lowest level in 40 years. In 2014, 40% of the population lived below the poverty line (defined by INSEE as 60% of Metropolitan France 's median income; in 2014 the poverty line for a family of two parents and two young children was €2,064 (US$2,743) per month). Rum distillation contributes to the island's economy. A " Product of France ", it is shipped to Europe for bottling, then shipped to consumers around the world. Brasseries de Bourbon is the main brewery of the island, with Heineken as shareholder. Income from tourism is Réunion Island's primary economic resource, ahead of sugarcane production and processing, which has allowed the development of large Réunionese groups such as Quartier Français, Groupe Bourbon ex-Sucreries Bourbon, a large international company now listed on the stock exchange , but based outside the island and which has abandoned the sugar sector for the off-shore maritime sector. With the reduction of subsidies, this culture is threatened. Therefore, the development of fishing in the French Southern Territories has been promoted. The tertiary sector , particularly the commercial sector, is by far the most developed, and import distribution has taken off in the mid-1980s through affiliation and franchising agreements with metropolitan groups. The advent of franchised distribution has transformed the commercial apparatus, which historically was characterized by the geographic dispersion of small grocery-type units; the few "Chinese stores" still in operation are limited to mid-range towns and, as relics of a bygone era, have more of a tourist and educational appeal, even if they retain a convenience store function. Despite its economic dynamism, the island is unable to absorb its significant unemployment, which is explained in particular by a very strong demographic growth. Many Réunioners are forced to move to metropolitan France for their studies or to find work. Agriculture in Réunion is an important activity in the island's economy: the agricultural territory covering 20% of the island's surface area employs 10% of the active population, generates 5% of the gross regional product and provides the island's main export. Formerly centered on coffee and clove cultivation, it has focused on sugar cane since the events of the early 19th century, namely the Great Avalanches and the seizure of Réunion by the British . Today it faces important issues related to the decisions of the World Trade Organization at the international level and the development of the urban fact at the local level. Réunion Island has about 7,000 farms, 5,000 of which are professional. These farms mobilize almost 11,000 AWU (annual workload of one person on a full-time basis). Ninety-seven percent of the farms in Réunion are less than 20 hectares in size, compared to an average of 78 hectares in mainland France . The most common status is that of individual farmer (97%). In 2005, more than 60% of farm managers were between 40 and 59 years old.Income from tourism is Réunion Island's primary economic resource, ahead of sugarcane production and processing, which has allowed the development of large Réunionese groups such as Quartier Français, Groupe Bourbon ex-Sucreries Bourbon, a large international company now listed on the stock exchange , but based outside the island and which has abandoned the sugar sector for the off-shore maritime sector. With the reduction of subsidies, this culture is threatened. Therefore, the development of fishing in the French Southern Territories has been promoted. The tertiary sector , particularly the commercial sector, is by far the most developed, and import distribution has taken off in the mid-1980s through affiliation and franchising agreements with metropolitan groups. The advent of franchised distribution has transformed the commercial apparatus, which historically was characterized by the geographic dispersion of small grocery-type units; the few "Chinese stores" still in operation are limited to mid-range towns and, as relics of a bygone era, have more of a tourist and educational appeal, even if they retain a convenience store function. Despite its economic dynamism, the island is unable to absorb its significant unemployment, which is explained in particular by a very strong demographic growth. Many Réunioners are forced to move to metropolitan France for their studies or to find work.Agriculture in Réunion is an important activity in the island's economy: the agricultural territory covering 20% of the island's surface area employs 10% of the active population, generates 5% of the gross regional product and provides the island's main export. Formerly centered on coffee and clove cultivation, it has focused on sugar cane since the events of the early 19th century, namely the Great Avalanches and the seizure of Réunion by the British . Today it faces important issues related to the decisions of the World Trade Organization at the international level and the development of the urban fact at the local level. Réunion Island has about 7,000 farms, 5,000 of which are professional. These farms mobilize almost 11,000 AWU (annual workload of one person on a full-time basis). Ninety-seven percent of the farms in Réunion are less than 20 hectares in size, compared to an average of 78 hectares in mainland France . The most common status is that of individual farmer (97%). In 2005, more than 60% of farm managers were between 40 and 59 years old.In 2005–2006, Réunion experienced an epidemic of chikungunya , a viral disease similar to dengue fever brought in from East Africa, which infected almost a third of the population because of its transmission through mosquitoes. The epidemic has since been eradicated. See the History section for more details. Roland Garros Airport serves the island, handling flights to mainland France, India, Madagascar , Mauritius , Tanzania , Comoros , Seychelles , South Africa, China and Thailand . Pierrefonds Airport , a smaller airport, has some flights to Mauritius and Madagascar. In 2019 a light rail system was proposed to link Le Barachois with the airport. Réunion Island has its own education system . Chantal Manès-Bonnisseau, Inspector General of Education, Sport and Research, was appointed Rector of the Académie de la Réunion and Chancellor of Universities at the Council of Ministers on 29 July 2020. She succeeds Vêlayoudom Marimoutou, who took office as secretary general of the Indian Ocean Commission on 16 July. The Rectorate is located in the main city, in the Moufia district of Saint-Denis. At the start of the 2012 school year, the island had 522 pre-school and/or primary schools, including 26 private schools, for 120,230 students at the primary level, 82 secondary schools, including six private schools, for 61,300 students, 32 general and technological high schools, including three private schools, for 23,650 students, and 15 vocational schools, including two private schools, for 16,200 students. Réunion's priority education zones affect slightly more than half of the primary and secondary school students. Baccalaureate results are relatively close to the national average with a rate of 81.4% in 2012 compared to 82.4% in 2011 (respectively: 84.5% and 85.6% in the national average). In higher education, the University of Réunion has 11,600 students spread across the various sites, especially in Saint-Denis and Le Tampon. A further 5,800 students are divided between the post-baccalaureate courses of secondary education and other higher studies. Energy on Réunion depends on oil and is limited by the island's insularity , which forces it to produce electricity locally and import fossil fuels . Faced with increasing demand and environmental requirements, the energy produced on the island is tending to increasingly exploit its great renewable energy potential through the development of wind farms , solar farms and other experimental projects. Although 35% of Réunion's electricity came from renewable sources in 2013, the department's energy dependency rate exceeds 85%. Saving electricity and optimising energy efficiency are two major areas of work for the authorities responsible for energy issues. Due to the large volumes of rainfall, the flow of surface water allows the installation of hydroelectric infrastructures, especially as erosion has carved out narrow and very deep ravines. The Sainte-Rose plant (22 MW) and the Takamaka plant (17.5 MW ) are the two largest. In total, the island's six hydroelectric infrastructures have a capacity of 133 MW.In 2005–2006, Réunion experienced an epidemic of chikungunya , a viral disease similar to dengue fever brought in from East Africa, which infected almost a third of the population because of its transmission through mosquitoes. The epidemic has since been eradicated. See the History section for more details.Roland Garros Airport serves the island, handling flights to mainland France, India, Madagascar , Mauritius , Tanzania , Comoros , Seychelles , South Africa, China and Thailand . Pierrefonds Airport , a smaller airport, has some flights to Mauritius and Madagascar. In 2019 a light rail system was proposed to link Le Barachois with the airport. Réunion Island has its own education system . Chantal Manès-Bonnisseau, Inspector General of Education, Sport and Research, was appointed Rector of the Académie de la Réunion and Chancellor of Universities at the Council of Ministers on 29 July 2020. She succeeds Vêlayoudom Marimoutou, who took office as secretary general of the Indian Ocean Commission on 16 July. The Rectorate is located in the main city, in the Moufia district of Saint-Denis. At the start of the 2012 school year, the island had 522 pre-school and/or primary schools, including 26 private schools, for 120,230 students at the primary level, 82 secondary schools, including six private schools, for 61,300 students, 32 general and technological high schools, including three private schools, for 23,650 students, and 15 vocational schools, including two private schools, for 16,200 students. Réunion's priority education zones affect slightly more than half of the primary and secondary school students. Baccalaureate results are relatively close to the national average with a rate of 81.4% in 2012 compared to 82.4% in 2011 (respectively: 84.5% and 85.6% in the national average). In higher education, the University of Réunion has 11,600 students spread across the various sites, especially in Saint-Denis and Le Tampon. A further 5,800 students are divided between the post-baccalaureate courses of secondary education and other higher studies. Energy on Réunion depends on oil and is limited by the island's insularity , which forces it to produce electricity locally and import fossil fuels . Faced with increasing demand and environmental requirements, the energy produced on the island is tending to increasingly exploit its great renewable energy potential through the development of wind farms , solar farms and other experimental projects. Although 35% of Réunion's electricity came from renewable sources in 2013, the department's energy dependency rate exceeds 85%. Saving electricity and optimising energy efficiency are two major areas of work for the authorities responsible for energy issues. Due to the large volumes of rainfall, the flow of surface water allows the installation of hydroelectric infrastructures, especially as erosion has carved out narrow and very deep ravines. The Sainte-Rose plant (22 MW) and the Takamaka plant (17.5 MW ) are the two largest. In total, the island's six hydroelectric infrastructures have a capacity of 133 MW.Due to the large volumes of rainfall, the flow of surface water allows the installation of hydroelectric infrastructures, especially as erosion has carved out narrow and very deep ravines. The Sainte-Rose plant (22 MW) and the Takamaka plant (17.5 MW ) are the two largest. In total, the island's six hydroelectric infrastructures have a capacity of 133 MW.Réunion has no official coat of arms or flag . Former Governor Merwart created a coat of arms for the island on the occasion of the 1925 colonial exhibition organised on Petite-Île. Merwart, a member of the Réunion Island Society of Sciences and Arts, wanted to include the island's history: The most commonly used flag in Réunion is that of the "radiant volcano", designed by Guy Pignolet in 1975, sometimes called "Lo Mavéli": it represents the volcano of Piton de la Fournaise in the form of a simplified red triangle on a navy blue background, while five sunbeams symbolise the arrival of the populations that have converged on the island over the centuries.

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Chikungunya

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Global Virus Network

The Global Virus Network ( GVN ) is an international coalition of medical virologists whose goal is to help the international medical community by improving the detection and management of viral diseases. The network was founded in 2011 by Robert Gallo in collaboration with William Hall and Reinhard Kurth, and 24 countries were members of the network as of 2015 [ update ] . The GVN fosters research into viruses that cause human disease to promote the development of diagnostics , antiviral drugs and vaccines , and its mission includes strengthening scientific training and response mechanisms to viral outbreaks. The GVN has organized task forces for chikungunya , human T-lymphotropic virus , and Zika . The network is headquartered at the Institute of Human Virology at the University of Maryland School of Medicine , and Gallo serves as its scientific director. The network's main mission is to tackle current broad viral threats as they develop, and to strengthen current research of viruses that cause human disease so as to prepare for any viral hazards. Their mission is outlined by 3 steps that they take to achieve it, which are international collective research, ongoing training of upcoming generations of medical virologists (public education), and advocacy. The GVN has grown to be a fundamental defense against diseases of viral nature. The GVN uses small grants to provide training fellowships so virologists can address current viral challenges. Global partnerships and mutual cooperation allows the GVN to span globally and to research viruses as they manifest and spread. [ citation needed ] The GVN is also a source of credible information about viruses, vaccines, and breakthroughs in both fields, which they spread through digital and public speaking platforms. The GVN promotes educational and valuable programs for future generations of scientists and biologists, and is a stable resource for both large governments and small organizations attempting to prepare themselves for viral threats. The final part of the GVN's mission is ensuring that funding persists, and that the network is able to provide up to date information through partnerships with governments and agencies across the world. The GVN also advocates for further virology research to be performed and for more virology training opportunities worldwide. [ citation needed ]The GVN uses small grants to provide training fellowships so virologists can address current viral challenges. Global partnerships and mutual cooperation allows the GVN to span globally and to research viruses as they manifest and spread. [ citation needed ]The GVN is also a source of credible information about viruses, vaccines, and breakthroughs in both fields, which they spread through digital and public speaking platforms. The GVN promotes educational and valuable programs for future generations of scientists and biologists, and is a stable resource for both large governments and small organizations attempting to prepare themselves for viral threats. The final part of the GVN's mission is ensuring that funding persists, and that the network is able to provide up to date information through partnerships with governments and agencies across the world. The GVN also advocates for further virology research to be performed and for more virology training opportunities worldwide. [ citation needed ]All scientists and their research under the GVN are supported through various continuous small grants. The GVN works with governments as well as research companies to ensure that funding for both virology training and research are kept high enough to meet the demands of global health. The GVN also receives funding from its partners, the Global Health Security Agenda (GHSA), the Coalition for Epidemic Preparedness Innovations (CEPI), and the Medical Technology Enterprise Consortium (MTEC). The GVN has 34 centers across 17 nations, each of which has a medical virologist as its director who is willing to commit to GVN's mission. Each center also specializes in at least two areas of viral science. Source: Manipal Institute of VirologySource: Manipal Institute of VirologyManipal Institute of VirologyCHIKV is a rapid-working onset febrile illness, of which the first visible symptom is a rash on the hands and arms. The virus causes a high fever and has the same intensity as that of an acute viral infection, similar to any virus present and visible in the bloodstream. The GVN was initially formed in 2011 in response to the outbreak of the Chikungunya virus, when it had just spread to the Western Hemisphere. While the GVN also discussed tackling the ongoing Ebola crisis centered around West Africa, the Chikungunya virus was their main priority at the time. CHIKV was discovered a little before 1968, and outbreaks had taken place everywhere from Thailand to the French Island of Réunion , where the virus at the time had caused 254 deaths. In 2013, the virus began to spread to the Caribbean and across the Atlantic to South America. The GVN is working toward antiviral drugs and vaccines against the Chikungunya virus, however one problem that the GVN has faced from the beginning is the limited ability to diagnose patients with the virus. As a result, the GVN was unable to control outbreaks in regions where the virus was most prominent because. However, so far the GVN has advanced the knowledge about the CHIKV infections, and has helped create a list of preventative measures which can be taken to stop the virus. In response to the ability of the virus to spread much more rapidly than initially thought, the GVN advanced efforts to learn more about and stop the virus. The network enlisted a task force to research CHIKV, for which researchers were selected based on their personal research, qualifications, and accomplishments. The task force is made up of 22 members, 3 co-chairs, and is overseen by Scott Weaver, John Fazakerley, and Marc Lecuit. The task force had 4 main tasks for the Chikungunya virus: to find funding for CHIKV research, distribute information to journalists and health officials, advocate for more research on virus-carrying mosquitos, and to review the science of the disease in order to identify vaccines and to start drug trials. Zika is a fast-acting virus that can be transferred through mosquito bites, and from a pregnant woman to her fetus. Currently, no vaccines or specific medication exist to treat the symptoms associated with the Zika virus, however there are general medications which limit the common symptoms of the virus. Common symptoms include fever, rash, headache joint pain, red eyes, and muscle pain. Symptoms typically don't last more than a week and people rarely die from this virus. However, the virus poses a threat if it gets transferred to a fetus as it can cause birth defects, miscarriages, and stillbirths. The GVN also assembled a task force to tackle the Zika virus. Unlike the CHIKV task force, Membership to this task force is voluntary, and any GVN member who has research or new developments that can be used in response to the Zika virus epidemic could contribute it. Scott Weaver acts as chairman to the Zika task force, which reports to all GVN centers regarding news and information about the virus. The GVN's main goal is to be control outbreaks and contain them to one general area so the virus is easier to diagnose, control, and possibly treat. HTLV-1 affects one's T-cells , though the virus usually causes no visible signs or symptoms. However, severe symptoms include motor changes in your limbs, an inflamed spinal cord, weakened legs, and cognitive impairment. Some people affected by the infection can develop adult T-cell Leukemia and can be predisposed to other severe medical conditions. This virus can spread through sexual contact, unsterile needles, and blood transfusions. It can also spread to a child from the mother's breast milk. There currently exist no treatments or cures for HTLV-1, and the condition lasts for a lifetime. However, it is not a major threat as roughly 95% of those infected are asymptomatic their whole life. The GVN has stated the importance of its work, which brings together the global community to conduct research and communicate about these viral problems that do not receive appropriate recognition in some areas. The task force made up of experts working on the HTLV-1 virus spans 11 countries, and is led by Dr. Robert Gallow in Maryland, Dr. Luc Willems in Belgium, and Dr. Hideki Hasegawa in Japan . The task force works daily to conduct research to hopefully stop HTLV-1, and the mission of the task force also includes funding drugs which can work to stop the virus from progressing into a disease . CHIKV is a rapid-working onset febrile illness, of which the first visible symptom is a rash on the hands and arms. The virus causes a high fever and has the same intensity as that of an acute viral infection, similar to any virus present and visible in the bloodstream. The GVN was initially formed in 2011 in response to the outbreak of the Chikungunya virus, when it had just spread to the Western Hemisphere. While the GVN also discussed tackling the ongoing Ebola crisis centered around West Africa, the Chikungunya virus was their main priority at the time. CHIKV was discovered a little before 1968, and outbreaks had taken place everywhere from Thailand to the French Island of Réunion , where the virus at the time had caused 254 deaths. In 2013, the virus began to spread to the Caribbean and across the Atlantic to South America. The GVN is working toward antiviral drugs and vaccines against the Chikungunya virus, however one problem that the GVN has faced from the beginning is the limited ability to diagnose patients with the virus. As a result, the GVN was unable to control outbreaks in regions where the virus was most prominent because. However, so far the GVN has advanced the knowledge about the CHIKV infections, and has helped create a list of preventative measures which can be taken to stop the virus. In response to the ability of the virus to spread much more rapidly than initially thought, the GVN advanced efforts to learn more about and stop the virus. The network enlisted a task force to research CHIKV, for which researchers were selected based on their personal research, qualifications, and accomplishments. The task force is made up of 22 members, 3 co-chairs, and is overseen by Scott Weaver, John Fazakerley, and Marc Lecuit. The task force had 4 main tasks for the Chikungunya virus: to find funding for CHIKV research, distribute information to journalists and health officials, advocate for more research on virus-carrying mosquitos, and to review the science of the disease in order to identify vaccines and to start drug trials. CHIKV is a rapid-working onset febrile illness, of which the first visible symptom is a rash on the hands and arms. The virus causes a high fever and has the same intensity as that of an acute viral infection, similar to any virus present and visible in the bloodstream. The GVN was initially formed in 2011 in response to the outbreak of the Chikungunya virus, when it had just spread to the Western Hemisphere. While the GVN also discussed tackling the ongoing Ebola crisis centered around West Africa, the Chikungunya virus was their main priority at the time. CHIKV was discovered a little before 1968, and outbreaks had taken place everywhere from Thailand to the French Island of Réunion , where the virus at the time had caused 254 deaths. In 2013, the virus began to spread to the Caribbean and across the Atlantic to South America. The GVN is working toward antiviral drugs and vaccines against the Chikungunya virus, however one problem that the GVN has faced from the beginning is the limited ability to diagnose patients with the virus. As a result, the GVN was unable to control outbreaks in regions where the virus was most prominent because. However, so far the GVN has advanced the knowledge about the CHIKV infections, and has helped create a list of preventative measures which can be taken to stop the virus. In response to the ability of the virus to spread much more rapidly than initially thought, the GVN advanced efforts to learn more about and stop the virus. The network enlisted a task force to research CHIKV, for which researchers were selected based on their personal research, qualifications, and accomplishments. The task force is made up of 22 members, 3 co-chairs, and is overseen by Scott Weaver, John Fazakerley, and Marc Lecuit. The task force had 4 main tasks for the Chikungunya virus: to find funding for CHIKV research, distribute information to journalists and health officials, advocate for more research on virus-carrying mosquitos, and to review the science of the disease in order to identify vaccines and to start drug trials. Zika is a fast-acting virus that can be transferred through mosquito bites, and from a pregnant woman to her fetus. Currently, no vaccines or specific medication exist to treat the symptoms associated with the Zika virus, however there are general medications which limit the common symptoms of the virus. Common symptoms include fever, rash, headache joint pain, red eyes, and muscle pain. Symptoms typically don't last more than a week and people rarely die from this virus. However, the virus poses a threat if it gets transferred to a fetus as it can cause birth defects, miscarriages, and stillbirths. The GVN also assembled a task force to tackle the Zika virus. Unlike the CHIKV task force, Membership to this task force is voluntary, and any GVN member who has research or new developments that can be used in response to the Zika virus epidemic could contribute it. Scott Weaver acts as chairman to the Zika task force, which reports to all GVN centers regarding news and information about the virus. The GVN's main goal is to be control outbreaks and contain them to one general area so the virus is easier to diagnose, control, and possibly treat. Zika is a fast-acting virus that can be transferred through mosquito bites, and from a pregnant woman to her fetus. Currently, no vaccines or specific medication exist to treat the symptoms associated with the Zika virus, however there are general medications which limit the common symptoms of the virus. Common symptoms include fever, rash, headache joint pain, red eyes, and muscle pain. Symptoms typically don't last more than a week and people rarely die from this virus. However, the virus poses a threat if it gets transferred to a fetus as it can cause birth defects, miscarriages, and stillbirths. The GVN also assembled a task force to tackle the Zika virus. Unlike the CHIKV task force, Membership to this task force is voluntary, and any GVN member who has research or new developments that can be used in response to the Zika virus epidemic could contribute it. Scott Weaver acts as chairman to the Zika task force, which reports to all GVN centers regarding news and information about the virus. The GVN's main goal is to be control outbreaks and contain them to one general area so the virus is easier to diagnose, control, and possibly treat. HTLV-1 affects one's T-cells , though the virus usually causes no visible signs or symptoms. However, severe symptoms include motor changes in your limbs, an inflamed spinal cord, weakened legs, and cognitive impairment. Some people affected by the infection can develop adult T-cell Leukemia and can be predisposed to other severe medical conditions. This virus can spread through sexual contact, unsterile needles, and blood transfusions. It can also spread to a child from the mother's breast milk. There currently exist no treatments or cures for HTLV-1, and the condition lasts for a lifetime. However, it is not a major threat as roughly 95% of those infected are asymptomatic their whole life. The GVN has stated the importance of its work, which brings together the global community to conduct research and communicate about these viral problems that do not receive appropriate recognition in some areas. The task force made up of experts working on the HTLV-1 virus spans 11 countries, and is led by Dr. Robert Gallow in Maryland, Dr. Luc Willems in Belgium, and Dr. Hideki Hasegawa in Japan . The task force works daily to conduct research to hopefully stop HTLV-1, and the mission of the task force also includes funding drugs which can work to stop the virus from progressing into a disease . HTLV-1 affects one's T-cells , though the virus usually causes no visible signs or symptoms. However, severe symptoms include motor changes in your limbs, an inflamed spinal cord, weakened legs, and cognitive impairment. Some people affected by the infection can develop adult T-cell Leukemia and can be predisposed to other severe medical conditions. This virus can spread through sexual contact, unsterile needles, and blood transfusions. It can also spread to a child from the mother's breast milk. There currently exist no treatments or cures for HTLV-1, and the condition lasts for a lifetime. However, it is not a major threat as roughly 95% of those infected are asymptomatic their whole life. The GVN has stated the importance of its work, which brings together the global community to conduct research and communicate about these viral problems that do not receive appropriate recognition in some areas. The task force made up of experts working on the HTLV-1 virus spans 11 countries, and is led by Dr. Robert Gallow in Maryland, Dr. Luc Willems in Belgium, and Dr. Hideki Hasegawa in Japan . The task force works daily to conduct research to hopefully stop HTLV-1, and the mission of the task force also includes funding drugs which can work to stop the virus from progressing into a disease .

Wiki

Chikungunya

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Ivermectin

AU : B3 22,23-dihydroavermectin B 1a + 22,23-dihydroavermectin B 1b 875.106 g·mol −1 (22,23-dihydroavermectin B 1a ) 861.079 g·mol −1 (22,23-dihydroavermectin B 1b ) CC[C@H](C)[C@@H]1[C@H](CC[C@@]2(O1)C[C@@H]3C[C@H](O2)C/C=C(/[C@H]([C@H](/C=C/C=C/4\CO[C@H]5[C@@]4([C@@H](C=C([C@H]5O)C)C(=O)O3)O)C)O[C@H]6C[C@@H]([C@H]([C@@H](O6)C)O[C@H]7C[C@@H]([C@H]([C@@H](O7)C)O)OC)OC)\C)C.C[C@H]1CC[C@]2(C[C@@H]3C[C@H](O2)C/C=C(/[C@H]([C@H](/C=C/C=C/4\CO[C@H]5[C@@]4([C@@H](C=C([C@H]5O)C)C(=O)O3)O)C)O[C@H]6C[C@@H]([C@H]([C@@H](O6)C)O[C@H]7C[C@@H]([C@H]([C@@H](O7)C)O)OC)OC)\C)O[C@@H]1C(C)C InChI=1S/C48H74O14.C47H72O14/c1-11-25(2)43-28(5)17-18-47(62-43)23-34-20-33(61-47)16-15-27(4)42(26(3)13-12-14-32-24-55-45-40(49)29(6)19-35(46(51)58-34)48(32,45)52)59-39-22-37(54-10)44(31(8)57-39)60-38-21-36(53-9)41(50)30(7)56-38;1-24(2)41-27(5)16-17-46(61-41)22-33-19-32(60-46)15-14-26(4)42(25(3)12-11-13-31-23-54-44-39(48)28(6)18–34(45(50)57-33)47(31,44)51)58-38-21-36(53–10)43(30(8)56–38)59-37-20-35(52–9)40(49)29(7)55-37/h12-15,19,25-26,28,30-31,33-45,49-50,52H,11,16-18,20-24H2,1-10H3;11-14,18,24-25,27,29-30,32-44,48-49,51H,15-17,19-23H2,1-10H3/b13-12+,27-15+,32-14+;12-11+,26-14+,31-13+/t25-,26-,28-,30-,31-,33+,34-,35-,36-,37-,38-,39-,40+,41-,42-,43+,44-,45+,47+,48+;25-,27-,29-,30-,32+,33-,34-,35-,36-,37-,38-,39+,40-,41+,42-,43-,44+,46+,47+/m00/s1 Y Key:SPBDXSGPUHCETR-JFUDTMANSA-N Y Ivermectin is an antiparasitic drug . After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis . Approved for human use in 1987, it is used to treat infestations including head lice , scabies , river blindness (onchocerciasis), strongyloidiasis , trichuriasis , ascariasis and lymphatic filariasis . It works through many mechanisms to kill the targeted parasites, and can be taken by mouth , or applied to the skin for external infestations. It belongs to the avermectin family of medications. William Campbell and Satoshi Ōmura won the 2015 Nobel Prize in Physiology or Medicine for its discovery and applications. It is on the World Health Organization's List of Essential Medicines , and is approved by the U.S. Food and Drug Administration as an antiparasitic agent . In 2021, it was the 341st most commonly prescribed medication in the United States, with more than 100,000 prescriptions. It is available as a generic medicine . During the COVID-19 pandemic , misinformation has been widely spread claiming that ivermectin is beneficial for treating and preventing COVID-19 . Such claims are not backed by credible scientific evidence. Multiple major health organizations, including the U.S. Food and Drug Administration, the U.S. Centers for Disease Control and Prevention , the European Medicines Agency , and the World Health Organization have stated that ivermectin is not authorized or approved to treat COVID-19. Ivermectin is used to treat human diseases caused by roundworms and a wide variety of external parasites . For river blindness (onchocerciasis) and lymphatic filariasis , ivermectin is typically given as part of mass drug administration campaigns that distribute the drug to all members of a community affected by the disease. Adult worms survive in the skin and eventually recover to produce larval worms again; to keep the worms at bay, ivermectin is given at least once per year for the 10 – 15-year lifespan of the adult worms. The World Health Organization (WHO) considers ivermectin the drug of choice for strongyloidiasis . Ivermectin is also the primary treatment for Mansonella ozzardi and cutaneous larva migrans . The U.S. Centers for Disease Control and Prevention (CDC) recommends ivermectin, albendazole, or mebendazole as treatments for ascariasis . [note 1] Ivermectin is sometimes added to albendazole or mebendazole for whipworm treatment, and is considered a second-line treatment for gnathostomiasis . Ivermectin is also used to treat infection with parasitic arthropods. Scabies – infestation with the mite Sarcoptes scabiei – is most commonly treated with topical permethrin or oral ivermectin. A single application of permethrin is more efficacious than a single treatment of ivermectin. For most scabies cases, ivermectin is used in a two dose regimen: a first dose kills the active mites, but not their eggs. Over the next week, the eggs hatch, and a second dose kills the newly hatched mites. The two dose regimen of ivermectin has similar efficacy to the single dose permethrin treatment. Ivermectin is, however, more effective than permethrin when used in the mass treatment of endemic scabies. For severe "crusted scabies", where the parasite burden is orders of magnitude higher than usual, the U.S. Centers for Disease Control and Prevention (CDC) recommends up to seven doses of ivermectin over the course of a month, along with a topical antiparasitic. Both head lice and pubic lice can be treated with oral ivermectin, an ivermectin lotion applied directly to the affected area, or various other insecticides. Ivermectin is also used to treat rosacea and blepharitis , both of which can be caused or exacerbated by Demodex folliculorum mites. For river blindness (onchocerciasis) and lymphatic filariasis , ivermectin is typically given as part of mass drug administration campaigns that distribute the drug to all members of a community affected by the disease. Adult worms survive in the skin and eventually recover to produce larval worms again; to keep the worms at bay, ivermectin is given at least once per year for the 10 – 15-year lifespan of the adult worms. The World Health Organization (WHO) considers ivermectin the drug of choice for strongyloidiasis . Ivermectin is also the primary treatment for Mansonella ozzardi and cutaneous larva migrans . The U.S. Centers for Disease Control and Prevention (CDC) recommends ivermectin, albendazole, or mebendazole as treatments for ascariasis . [note 1] Ivermectin is sometimes added to albendazole or mebendazole for whipworm treatment, and is considered a second-line treatment for gnathostomiasis . Ivermectin is also used to treat infection with parasitic arthropods. Scabies – infestation with the mite Sarcoptes scabiei – is most commonly treated with topical permethrin or oral ivermectin. A single application of permethrin is more efficacious than a single treatment of ivermectin. For most scabies cases, ivermectin is used in a two dose regimen: a first dose kills the active mites, but not their eggs. Over the next week, the eggs hatch, and a second dose kills the newly hatched mites. The two dose regimen of ivermectin has similar efficacy to the single dose permethrin treatment. Ivermectin is, however, more effective than permethrin when used in the mass treatment of endemic scabies. For severe "crusted scabies", where the parasite burden is orders of magnitude higher than usual, the U.S. Centers for Disease Control and Prevention (CDC) recommends up to seven doses of ivermectin over the course of a month, along with a topical antiparasitic. Both head lice and pubic lice can be treated with oral ivermectin, an ivermectin lotion applied directly to the affected area, or various other insecticides. Ivermectin is also used to treat rosacea and blepharitis , both of which can be caused or exacerbated by Demodex folliculorum mites. The only absolute contraindication to the use of ivermectin is hypersensitivity to the active ingredient or any component of the formulation. In children under the age of five or those who weigh less than 15 kilograms (33 pounds) , there is limited data regarding the efficacy or safety of ivermectin, though the available data demonstrate few adverse effects. However, the American Academy of Pediatrics cautions against use of ivermectin in such patients, as the blood-brain barrier is less developed, and thus there may be an increased risk of particular CNS side effects such as encephalopathy, ataxia, coma, or death. The American Academy of Family Physicians also recommends against use in these patients, given a lack of sufficient data to prove drug safety. Ivermectin is secreted in very low concentration in breast milk. It remains unclear if ivermectin is safe during pregnancy. Side effects, although uncommon, include fever, itching, and skin rash when taken by mouth; and red eyes , dry skin, and burning skin when used topically for head lice. It is unclear if the drug is safe for use during pregnancy , but it is probably acceptable for use during breastfeeding . Ivermectin is considered relatively free of toxicity in standard doses (around 300 µg/kg). Based on the data drug safety sheet for ivermectin, [lower-alpha 1] side effects are uncommon. However, serious adverse events following ivermectin treatment are more common in people with very high burdens of larval Loa loa worms in their blood. Those who have over 30,000 microfilaria per milliliter of blood risk inflammation and capillary blockage due to the rapid death of the microfilaria following ivermectin treatment. One concern is neurotoxicity after large overdoses, which in most mammalian species may manifest as central nervous system depression , ataxia , coma, and even death, as might be expected from potentiation of inhibitory chloride channels. Since drugs that inhibit the enzyme CYP3A4 often also inhibit P-glycoprotein transport, the risk of increased absorption past the blood-brain barrier exists when ivermectin is administered along with other CYP3A4 inhibitors. These drugs include statins , HIV protease inhibitors , many calcium channel blockers , lidocaine , the benzodiazepines , and glucocorticoids such as dexamethasone . During the course of a typical treatment, ivermectin can cause minor aminotransferase elevations . In rare cases it can cause mild clinically apparent liver disease . To provide context for the dosing and toxicity ranges, the LD 50 of ivermectin in mice is 25 mg/kg (oral), and 80 mg/kg in dogs, corresponding to an approximated human-equivalent dose LD50 range of 2.02–43.24 mg/kg, which is far in excess of its FDA-approved usage (a single dose of 0.150–0.200 mg/kg to be used for specific parasitic infections). While ivermectin has also been studied for use in COVID-19, and while it has some ability to inhibit SARS-CoV-2 in vitro, achieving 50% inhibition in vitro was found to require an estimated oral dose of 7.0 mg/kg (or 35x the maximum FDA-approved dosage), high enough to be considered ivermectin poisoning. Despite insufficient data to show any safe and effective dosing regimen for ivermectin in COVID-19, doses have been taken far in excess of FDA-approved dosing, leading the CDC to issue a warning of overdose symptoms including nausea, vomiting, diarrhea, hypotension, decreased level of consciousness , confusion, blurred vision, visual hallucinations, loss of coordination and balance, seizures, coma, and death. The CDC advises against consuming doses intended for livestock or doses intended for external use and warns that increasing misuse of ivermectin-containing products is resulting in an increase in harmful overdoses. Ivermectin and its related drugs act by interfering with the nerve and muscle functions of helminths and insects. The drug binds to glutamate -gated chloride channels common to invertebrate nerve and muscle cells. The binding pushes the channels open, which increases the flow of chloride ions and hyper-polarizes the cell membranes, paralyzing and killing the invertebrate. Ivermectin is safe for mammals (at the normal therapeutic doses used to cure parasite infections) because mammalian glutamate-gated chloride channels only occur in the brain and spinal cord: the causative avermectins usually do not cross the blood–brain barrier , and are unlikely to bind to other mammalian ligand-gated channels . Ivermectin can be given by mouth, topically, or via injection. Oral doses are absorbed into systemic circulation; the alcoholic solution form is more orally available than tablet and capsule forms. Ivermectin is widely distributed in the body. Ivermectin does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein (the MDR1 gene mutation affects the function of this protein). Crossing may still become significant if ivermectin is given at high doses, in which case brain levels peak 2–5 hours after administration. In contrast to mammals, ivermectin can cross the blood–brain barrier in tortoises, often with fatal consequences. Ivermectin and its related drugs act by interfering with the nerve and muscle functions of helminths and insects. The drug binds to glutamate -gated chloride channels common to invertebrate nerve and muscle cells. The binding pushes the channels open, which increases the flow of chloride ions and hyper-polarizes the cell membranes, paralyzing and killing the invertebrate. Ivermectin is safe for mammals (at the normal therapeutic doses used to cure parasite infections) because mammalian glutamate-gated chloride channels only occur in the brain and spinal cord: the causative avermectins usually do not cross the blood–brain barrier , and are unlikely to bind to other mammalian ligand-gated channels . Ivermectin can be given by mouth, topically, or via injection. Oral doses are absorbed into systemic circulation; the alcoholic solution form is more orally available than tablet and capsule forms. Ivermectin is widely distributed in the body. Ivermectin does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein (the MDR1 gene mutation affects the function of this protein). Crossing may still become significant if ivermectin is given at high doses, in which case brain levels peak 2–5 hours after administration. In contrast to mammals, ivermectin can cross the blood–brain barrier in tortoises, often with fatal consequences. Fermentation of Streptomyces avermitilis yields eight closely related avermectin homologues , of which B 1a and B 1b form the bulk of the products isolated. In a separate chemical step, the mixture is hydrogenated to give ivermectin, which is an approximately 80:20 mixture of the two 22,23-dihydroavermectin compounds. Ivermectin is a macrocyclical lactone. The avermectin family of compounds was discovered by Satoshi Ōmura of Kitasato University and William Campbell of Merck . In 1970, Ōmura isolated a strain of Streptomyces avermitilis from woodland soil near a golf course along the south east coast of Honshu , Japan. Ōmura sent the bacteria to William Campbell, who showed that the bacterial culture could cure mice infected with the roundworm Heligmosomoides polygyrus . Campbell isolated the active compounds from the bacterial culture, naming them "avermectins" and the bacterium Streptomyces avermitilis for the compounds' ability to clear mice of worms (in Latin: a 'without', vermis 'worms'). Of the various avermectins, Campbell's group found the compound "avermectin B 1 " to be the most potent when taken orally. They synthesized modified forms of avermectin B 1 to improve its pharmaceutical properties, eventually choosing a mixture of at least 80% 22,23-dihydroavermectin B 1a and up to 20% 22,23-dihydroavermectin B 1b , a combination they called "ivermectin". The discovery of ivermectin has been described as a combination of "chance and choice." Merck was looking for a broad-spectrum anthelmintic, which ivermectin is indeed; however, Campbell noted that they "...also found a broad-spectrum agent for the control of ectoparasitic insects and mites." Merck began marketing ivermectin as a veterinary antiparasitic in 1981. By 1986, ivermectin was registered for use in 46 countries and was administered massively to cattle, sheep and other animals. By the late 1980s, ivermectin was the bestselling veterinary medicine in the world. Following its blockbuster success as a veterinary antiparasitic, another Merck scientist, Mohamed Aziz, collaborated with the World Health Organization to test the safety and efficacy of ivermectin against onchocerciasis in humans. They found it to be highly safe and effective, triggering Merck to register ivermectin for human use as "Mectizan" in France in 1987. A year later, Merck CEO Roy Vagelos agreed that Merck would donate all ivermectin needed to eradicate river blindness. In 1998, that donation would be expanded to include ivermectin used to treat lymphatic filariasis. Ivermectin earned the title of "wonder drug" for the treatment of nematodes and arthropod parasites. Ivermectin has been used safely by hundreds of millions of people to treat river blindness and lymphatic filariasis. Half of the 2015 Nobel Prize in Physiology or Medicine was awarded jointly to Campbell and Ōmura for discovering avermectin, "the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis , as well as showing efficacy against an expanding number of other parasitic diseases". Early in the COVID-19 pandemic , laboratory research suggested ivermectin might have a role in preventing or treating COVID-19. Online misinformation campaigns and advocacy boosted the drug's profile among the public. While scientists and physicians largely remained skeptical, some nations adopted ivermectin as part of their pandemic-control efforts. Some people, desperate to use ivermectin without a prescription, took veterinary preparations, which led to shortages of supplies of ivermectin for animal treatment. The FDA responded to this situation by saying "You are not a horse" in a Tweet to draw attention to the issue, which they were later sued for. The initial price proposed by Merck in 1987 was US$ 6 per treatment, which was unaffordable for patients who most needed ivermectin. The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries. Between 1995 and 2010, using donated ivermectin to prevent river blindness , the program is estimated to have prevented seven million years of disability at a cost of US$ 257 million . Ivermectin is considered an inexpensive drug. As of 2019, ivermectin tablets (Stromectol) in the United States were the least expensive treatment option for lice in children at approximately US$ 9.30 , while Sklice, an ivermectin lotion, cost around US$ 300 for 120 mL (4 US fl oz) . As of 2019 [ update ] , the cost effectiveness of treating scabies and lice with ivermectin has not been studied. It is sold under the brand names Heartgard, Sklice and Stromectol in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck , Iver-DT in Nepal by Alive Pharmaceutical and Ivexterm in Mexico by Valeant Pharmaceuticals International . In Southeast Asian countries, it is marketed by Delta Pharma Ltd. under the trade name Scabo 6. The formulation for rosacea treatment is sold under the brand name Soolantra. While in development, it was assigned the code MK-933 by Merck. Early in the COVID-19 pandemic , laboratory research suggested ivermectin might have a role in preventing or treating COVID-19. Online misinformation campaigns and advocacy boosted the drug's profile among the public. While scientists and physicians largely remained skeptical, some nations adopted ivermectin as part of their pandemic-control efforts. Some people, desperate to use ivermectin without a prescription, took veterinary preparations, which led to shortages of supplies of ivermectin for animal treatment. The FDA responded to this situation by saying "You are not a horse" in a Tweet to draw attention to the issue, which they were later sued for. The initial price proposed by Merck in 1987 was US$ 6 per treatment, which was unaffordable for patients who most needed ivermectin. The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries. Between 1995 and 2010, using donated ivermectin to prevent river blindness , the program is estimated to have prevented seven million years of disability at a cost of US$ 257 million . Ivermectin is considered an inexpensive drug. As of 2019, ivermectin tablets (Stromectol) in the United States were the least expensive treatment option for lice in children at approximately US$ 9.30 , while Sklice, an ivermectin lotion, cost around US$ 300 for 120 mL (4 US fl oz) . As of 2019 [ update ] , the cost effectiveness of treating scabies and lice with ivermectin has not been studied. It is sold under the brand names Heartgard, Sklice and Stromectol in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck , Iver-DT in Nepal by Alive Pharmaceutical and Ivexterm in Mexico by Valeant Pharmaceuticals International . In Southeast Asian countries, it is marketed by Delta Pharma Ltd. under the trade name Scabo 6. The formulation for rosacea treatment is sold under the brand name Soolantra. While in development, it was assigned the code MK-933 by Merck. Ivermectin has been researched in laboratory animals, as a potential treatment for trichinosis and trypanosomiasis . As of 2016 [ update ] ivermectin was studied as a potential antiviral agent against chikungunya and yellow fever . In chikungunya, ivermectin showed a wide in vitro safety margin as an antiviral. Ivermectin is also of interest in the prevention of malaria , as it is toxic to both the malaria plasmodium itself and the mosquitos that carry it. A direct effect on malaria parasites could not be shown in an experimental infection of volunteers with Plasmodium falciparum . Use of ivermectin at higher doses necessary to control malaria is probably safe, though large clinical trials have not yet been done to definitively establish the efficacy or safety of ivermectin for prophylaxis or treatment of malaria. Mass drug administration of a population with ivermectin to treat and prevent nematode infestation is effective for eliminating malaria-bearing mosquitos and thereby potentially reducing infection with residual malaria parasites . Whilst effective in killing malaria-bearing mosquitos, a 2021 Cochrane review found that, to date, the evidence shows no significant impact on reducing incidence of malaria transmission from the community administration of ivermectin. One alternative to ivermectin is moxidectin , which has been approved by the Food and Drug Administration for use in people with river blindness. Moxidectin has a longer half-life than ivermectin and may eventually supplant ivermectin as it is a more potent microfilaricide, but there is a need for additional clinical trials, with long-term follow-up, to assess whether moxidectin is safe and effective for treatment of nematode infection in children and women of childbearing potential. There is tentative evidence that ivermectin kills bedbugs , as part of integrated pest management for bedbug infestations . However, such use may require a prolonged course of treatment which is of unclear safety. In 2013, ivermectin was demonstrated as a novel ligand of the farnesoid X receptor , a therapeutic target for nonalcoholic fatty liver disease . During the COVID-19 pandemic, ivermectin was researched for possible utility in preventing and treating COVID-19, but no good evidence of benefit was found. Ivermectin has been researched in laboratory animals, as a potential treatment for trichinosis and trypanosomiasis . As of 2016 [ update ] ivermectin was studied as a potential antiviral agent against chikungunya and yellow fever . In chikungunya, ivermectin showed a wide in vitro safety margin as an antiviral. Ivermectin is also of interest in the prevention of malaria , as it is toxic to both the malaria plasmodium itself and the mosquitos that carry it. A direct effect on malaria parasites could not be shown in an experimental infection of volunteers with Plasmodium falciparum . Use of ivermectin at higher doses necessary to control malaria is probably safe, though large clinical trials have not yet been done to definitively establish the efficacy or safety of ivermectin for prophylaxis or treatment of malaria. Mass drug administration of a population with ivermectin to treat and prevent nematode infestation is effective for eliminating malaria-bearing mosquitos and thereby potentially reducing infection with residual malaria parasites . Whilst effective in killing malaria-bearing mosquitos, a 2021 Cochrane review found that, to date, the evidence shows no significant impact on reducing incidence of malaria transmission from the community administration of ivermectin. One alternative to ivermectin is moxidectin , which has been approved by the Food and Drug Administration for use in people with river blindness. Moxidectin has a longer half-life than ivermectin and may eventually supplant ivermectin as it is a more potent microfilaricide, but there is a need for additional clinical trials, with long-term follow-up, to assess whether moxidectin is safe and effective for treatment of nematode infection in children and women of childbearing potential. There is tentative evidence that ivermectin kills bedbugs , as part of integrated pest management for bedbug infestations . However, such use may require a prolonged course of treatment which is of unclear safety. In 2013, ivermectin was demonstrated as a novel ligand of the farnesoid X receptor , a therapeutic target for nonalcoholic fatty liver disease . During the COVID-19 pandemic, ivermectin was researched for possible utility in preventing and treating COVID-19, but no good evidence of benefit was found. Ivermectin is routinely used to control parasitic worms in the gastrointestinal tract of ruminant animals. These parasites normally enter the animal when it is grazing, pass the bowel, and set and mature in the intestines, after which they produce eggs that leave the animal via its droppings and can infest new pastures. Ivermectin is only effective in killing some of these parasites, this is because of an increase in anthelmintic resistance. This resistance has arisen from the persistent use of the same anthelmintic drugs for the past 40 years. In dogs, ivermectin is routinely used as prophylaxis against heartworm. Dogs with defects in the P-glycoprotein gene ( MDR1 ), often collie-like herding dogs, can be severely poisoned by ivermectin. The mnemonic "white feet, don't treat" refers to Scotch collies that are vulnerable to ivermectin. Some other dog breeds (especially the Rough Collie , the Smooth Collie , the Shetland Sheepdog , and the Australian Shepherd ), also have a high incidence of mutation within the MDR1 gene (coding for P-glycoprotein) and are sensitive to the toxic effects of ivermectin. Clinical evidence suggests 7-week-old kittens are susceptible to ivermectin toxicity. A 0.01% ivermectin topical preparation for treating ear mites in cats is available. Ivermectin is sometimes used as an acaricide in reptiles, both by injection and as a diluted spray. While this works well in some cases, care must be taken, as several species of reptiles are very sensitive to ivermectin. Use in turtles is particularly contraindicated. A characteristic of the antinematodal action of ivermectin is its potency: for instance, to combat Dirofilaria immitis in dogs, ivermectin is effective at 0.001 milligram per kilogram of body weight when administered orally. For dogs, the insecticide spinosad may have the effect of increasing the toxicity of ivermectin.

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COVID-19 vaccine

none A COVID ‑ 19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ), the virus that causes coronavirus disease 2019 ( COVID ‑ 19 ). Prior to the COVID‑19 pandemic , an established body of knowledge existed about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome ( SARS ) and Middle East respiratory syndrome ( MERS ). This knowledge accelerated the development of various vaccine platforms in early 2020. The initial focus of SARS-CoV-2 vaccines was on preventing symptomatic, often severe, illness. In 2020, the first COVID ‑ 19 vaccines were developed and made available to the public through emergency authorizations and conditional approvals. Initially, most COVID ‑ 19 vaccines were two-dose vaccines, with the sole exception being the single-dose Janssen COVID‑19 vaccine . However, immunity from the vaccines has been found to wane over time, requiring people to get booster doses of the vaccine to maintain protection against COVID ‑ 19. The COVID ‑ 19 vaccines are widely credited for their role in reducing the spread of COVID ‑ 19 and reducing the severity and death caused by COVID ‑ 19. According to a June 2022 study, COVID ‑ 19 vaccines prevented an additional 14.4 to 19.8 million deaths in 185 countries and territories from 8 December 2020 to 8 December 2021. Many countries implemented phased distribution plans that prioritized those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. Common side effects of COVID ‑ 19 vaccines include soreness, redness, rash, inflammation at the injection site, fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain), which resolve without medical treatment within a few days. COVID ‑ 19 vaccination is safe for people who are pregnant or are breastfeeding. As of 1 February 2024 [ update ] , 13.57 billion doses of COVID ‑ 19 vaccines have been administered worldwide, based on official reports from national public health agencies . By December 2020, more than 10 billion vaccine doses had been preordered by countries, with about half of the doses purchased by high-income countries comprising 14% of the world's population. Despite the extremely rapid development of effective mRNA and viral vector vaccines , worldwide vaccine equity has not been achieved. The development and use of whole inactivated virus (WIV) and protein-based vaccines have also been recommended, especially for use in developing countries . The 2023 Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for the development of effective mRNA vaccines against COVID-19. Prior to COVID ‑ 19, a vaccine for an infectious disease had never been produced in less than several years – and no vaccine existed for preventing a coronavirus infection in humans. However, vaccines have been produced against several animal diseases caused by coronaviruses, including (as of 2003) infectious bronchitis virus in birds, canine coronavirus , and feline coronavirus . Previous projects to develop vaccines for viruses in the family Coronaviridae that affect humans have been aimed at severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Vaccines against SARS and MERS have been tested in non-human animals . According to studies published in 2005 and 2006, the identification and development of novel vaccines and medicines to treat SARS was a priority for governments and public health agencies around the world at that time. There is no cure or protective vaccine proven to be safe and effective against SARS in humans. There is also no proven vaccine against MERS. When MERS became prevalent, it was believed that existing SARS research might provide a useful template for developing vaccines and therapeutics against a MERS-CoV infection. As of March 2020, there was one (DNA-based) MERS vaccine that completed Phase I clinical trials in humans, and three others in progress, all being viral-vectored vaccines: two adenoviral-vectored (ChAdOx1-MERS, BVRS-GamVac) and one MVA -vectored (MVA-MERS-S). Vaccines that use an inactive or weakened virus that has been grown in eggs typically take more than a decade to develop. In contrast, mRNA is a molecule that can be made quickly, and research on mRNA to fight diseases was begun decades before the COVID ‑ 19 pandemic by scientists such as Drew Weissman and Katalin Karikó , who tested on mice. Moderna began human testing of an mRNA vaccine in 2015. Viral vector vaccines were also developed for the COVID ‑ 19 pandemic after the technology was previously cleared for Ebola. As multiple COVID ‑ 19 vaccines have been authorized or licensed for use, real-world vaccine effectiveness (RWE) is being assessed using case control and observational studies. A study is investigating the long-lasting protection against SARS-CoV-2 provided by the mRNA vaccines. As of July 2021, at least nine different technology platforms were under research and development to create an effective vaccine against COVID ‑ 19. Most of the platforms of vaccine candidates in clinical trials are focused on the coronavirus spike protein (S protein) and its variants as the primary antigen of COVID ‑ 19 infection, since the S protein triggers strong B-cell and T-cell immune responses. However, other coronavirus proteins are also being investigated for vaccine development, like the nucleocapsid , because they also induce a robust T-cell response and their genes are more conserved and recombine less frequently (compared to Spike). Future generations of COVID ‑ 19 vaccines that may target more conserved genomic regions will also act as insurance against the manifestation of catastrophic scenarios concerning the future evolutionary path of SARS-CoV-2, or any similar coronavirus epidemic/pandemic. Platforms developed in 2020 involved nucleic acid technologies ( nucleoside-modified messenger RNA and DNA ), non-replicating viral vectors , peptides , recombinant proteins , live attenuated viruses , and inactivated viruses . Many vaccine technologies being developed for COVID ‑ 19 are not like influenza vaccines but rather use "next-generation" strategies for precise targeting of COVID ‑ 19 infection mechanisms. Several of the synthetic vaccines use a 2P mutation to lock the spike protein into its prefusion configuration, stimulating an adaptive immune response to the virus before it attaches to a human cell. Vaccine platforms in development may improve flexibility for antigen manipulation and effectiveness for targeting mechanisms of COVID ‑ 19 infection in susceptible population subgroups, such as healthcare workers, the elderly, children, pregnant women , and people with weakened immune systems . Several COVID ‑ 19 vaccines, such as the Pfizer–BioNTech and Moderna vaccines, use RNA to stimulate an immune response. When introduced into human tissue, the vaccine contains either self-replicating RNA or messenger RNA (mRNA), which both cause cells to express the SARS-CoV-2 spike protein . This teaches the body how to identify and destroy the corresponding pathogen. RNA vaccines often use nucleoside-modified messenger RNA . The delivery of mRNA is achieved by a coformulation of the molecule into lipid nanoparticles , which protect the RNA strands and help their absorption into the cells. RNA vaccines are the first COVID ‑ 19 vaccines to be authorized in the United Kingdom, the United States, and the European Union. Authorized vaccines of this type are the Pfizer–BioNTech and Moderna vaccines. The CVnCoV RNA vaccine from CureVac failed in clinical trials. Severe allergic reactions are rare. In December 2020, 1,893,360 first doses of Pfizer–BioNTech COVID ‑ 19 vaccine administration resulted in 175 cases of severe allergic reactions, of which 21 were anaphylaxis . For 4,041,396 Moderna COVID ‑ 19 vaccine dose administrations in December 2020 and January 2021, only ten cases of anaphylaxis were reported. Lipid nanoparticles (LNPs) were most likely responsible for the allergic reactions. These vaccines are examples of non-replicating viral vector vaccines using an adenovirus shell containing DNA that encodes a SARS‑CoV‑2 protein. The viral vector-based vaccines against COVID ‑ 19 are non-replicating, meaning that they do not make new virus particles but rather produce only the antigen that elicits a systemic immune response. Authorized vaccines of this type are the Oxford–AstraZeneca COVID‑19 vaccine , the Sputnik V COVID‑19 vaccine , Convidecia , and the Janssen COVID‑19 vaccine . Convidecia and Janssen are both one-shot vaccines that offer less complicated logistics and can be stored under ordinary refrigeration for several months. Sputnik V uses Ad26 for its first dose, which is the same as Janssen's only dose, and Ad5 for the second dose, which is the same as Convidecia's only dose. In August 2021, the developers of Sputnik V proposed, in view of the Delta case surge, that Pfizer test the Ad26 component (termed its 'Light' version) as a booster shot. Inactivated vaccines consist of virus particles that are grown in culture and then killed using a method such as heat or formaldehyde to lose disease-producing capacity while still stimulating an immune response. Inactivated virus vaccines authorized in China include the Chinese CoronaVac and the Sinopharm BIBP and WIBP vaccines; there is also the Indian Covaxin ; later this year, the Russian CoviVac ; the Kazakh vaccine QazVac ; and the Iranian COVIran Barekat . Vaccines in clinical trials include the Valneva COVID ‑ 19 vaccine . [ unreliable source? ] Subunit vaccines present one or more antigens without introducing whole pathogen particles. The antigens involved are often protein subunits , but they can be any molecule fragment of the pathogen. The authorized vaccines of this type are the peptide vaccine EpiVacCorona , ZF2001 , MVC-COV1901 , Corbevax , the Sanofi–GSK vaccine , and Soberana 02 (a conjugate vaccine ). Bimervax was approved for use as a booster vaccine in the European Union in March 2023. The V451 vaccine was in clinical trials that were terminated after it was found that the vaccine may potentially cause incorrect results for subsequent HIV testing. The authorized vaccines of this type include the Novavax COVID‑19 vaccine . Additional types of vaccines that are in clinical trials include multiple DNA plasmid vaccines , at least two lentivirus vector vaccines, a conjugate vaccine , and a vesicular stomatitis virus displaying the SARS‑CoV‑2 spike protein. Scientists investigated whether existing vaccines for unrelated conditions could prime the immune system and lessen the severity of COVID ‑ 19 infections. There is experimental evidence that the BCG vaccine for tuberculosis has non-specific effects on the immune system, but there is no evidence that this vaccine is effective against COVID ‑ 19. Several COVID ‑ 19 vaccines, such as the Pfizer–BioNTech and Moderna vaccines, use RNA to stimulate an immune response. When introduced into human tissue, the vaccine contains either self-replicating RNA or messenger RNA (mRNA), which both cause cells to express the SARS-CoV-2 spike protein . This teaches the body how to identify and destroy the corresponding pathogen. RNA vaccines often use nucleoside-modified messenger RNA . The delivery of mRNA is achieved by a coformulation of the molecule into lipid nanoparticles , which protect the RNA strands and help their absorption into the cells. RNA vaccines are the first COVID ‑ 19 vaccines to be authorized in the United Kingdom, the United States, and the European Union. Authorized vaccines of this type are the Pfizer–BioNTech and Moderna vaccines. The CVnCoV RNA vaccine from CureVac failed in clinical trials. Severe allergic reactions are rare. In December 2020, 1,893,360 first doses of Pfizer–BioNTech COVID ‑ 19 vaccine administration resulted in 175 cases of severe allergic reactions, of which 21 were anaphylaxis . For 4,041,396 Moderna COVID ‑ 19 vaccine dose administrations in December 2020 and January 2021, only ten cases of anaphylaxis were reported. Lipid nanoparticles (LNPs) were most likely responsible for the allergic reactions. These vaccines are examples of non-replicating viral vector vaccines using an adenovirus shell containing DNA that encodes a SARS‑CoV‑2 protein. The viral vector-based vaccines against COVID ‑ 19 are non-replicating, meaning that they do not make new virus particles but rather produce only the antigen that elicits a systemic immune response. Authorized vaccines of this type are the Oxford–AstraZeneca COVID‑19 vaccine , the Sputnik V COVID‑19 vaccine , Convidecia , and the Janssen COVID‑19 vaccine . Convidecia and Janssen are both one-shot vaccines that offer less complicated logistics and can be stored under ordinary refrigeration for several months. Sputnik V uses Ad26 for its first dose, which is the same as Janssen's only dose, and Ad5 for the second dose, which is the same as Convidecia's only dose. In August 2021, the developers of Sputnik V proposed, in view of the Delta case surge, that Pfizer test the Ad26 component (termed its 'Light' version) as a booster shot. Inactivated vaccines consist of virus particles that are grown in culture and then killed using a method such as heat or formaldehyde to lose disease-producing capacity while still stimulating an immune response. Inactivated virus vaccines authorized in China include the Chinese CoronaVac and the Sinopharm BIBP and WIBP vaccines; there is also the Indian Covaxin ; later this year, the Russian CoviVac ; the Kazakh vaccine QazVac ; and the Iranian COVIran Barekat . Vaccines in clinical trials include the Valneva COVID ‑ 19 vaccine . [ unreliable source? ] Subunit vaccines present one or more antigens without introducing whole pathogen particles. The antigens involved are often protein subunits , but they can be any molecule fragment of the pathogen. The authorized vaccines of this type are the peptide vaccine EpiVacCorona , ZF2001 , MVC-COV1901 , Corbevax , the Sanofi–GSK vaccine , and Soberana 02 (a conjugate vaccine ). Bimervax was approved for use as a booster vaccine in the European Union in March 2023. The V451 vaccine was in clinical trials that were terminated after it was found that the vaccine may potentially cause incorrect results for subsequent HIV testing. The authorized vaccines of this type include the Novavax COVID‑19 vaccine . Additional types of vaccines that are in clinical trials include multiple DNA plasmid vaccines , at least two lentivirus vector vaccines, a conjugate vaccine , and a vesicular stomatitis virus displaying the SARS‑CoV‑2 spike protein. Scientists investigated whether existing vaccines for unrelated conditions could prime the immune system and lessen the severity of COVID ‑ 19 infections. There is experimental evidence that the BCG vaccine for tuberculosis has non-specific effects on the immune system, but there is no evidence that this vaccine is effective against COVID ‑ 19. All coronavirus vaccines are administered by injection. However, various other types of vaccine delivery methods have been studied for future coronavirus vaccines. Intranasal vaccines target mucosal immunity in the nasal mucosa , which is a portal for viral entry into the body. These vaccines are designed to stimulate nasal immune factors , such as IgA . In addition to inhibiting the virus, nasal vaccines provide ease of administration because no needles (or needle phobia ) are involved. A variety of intranasal COVID ‑ 19 vaccines are undergoing clinical trials. One is in use in China. Examples include a vaccine candidate that uses a modified avian virus as a vector to target SARS-CoV-2 spike proteins and an mRNA vaccine delivered via a nasal nanoparticle spray. In September 2022, India and China approved the two first nasal COVID ‑ 19 vaccines ( iNCOVACC and Convidecia ), which may (as boosters) also reduce transmission (potentially via sterilizing immunity). Aivita Biomedical is developing an experimental autologous dendritic cell COVID ‑ 19 vaccine kit where the vaccine is prepared and incubated at the point-of-care using cells from the intended recipient. The vaccine is undergoing small phase I and phase II clinical studies. Intranasal vaccines target mucosal immunity in the nasal mucosa , which is a portal for viral entry into the body. These vaccines are designed to stimulate nasal immune factors , such as IgA . In addition to inhibiting the virus, nasal vaccines provide ease of administration because no needles (or needle phobia ) are involved. A variety of intranasal COVID ‑ 19 vaccines are undergoing clinical trials. One is in use in China. Examples include a vaccine candidate that uses a modified avian virus as a vector to target SARS-CoV-2 spike proteins and an mRNA vaccine delivered via a nasal nanoparticle spray. In September 2022, India and China approved the two first nasal COVID ‑ 19 vaccines ( iNCOVACC and Convidecia ), which may (as boosters) also reduce transmission (potentially via sterilizing immunity). Aivita Biomedical is developing an experimental autologous dendritic cell COVID ‑ 19 vaccine kit where the vaccine is prepared and incubated at the point-of-care using cells from the intended recipient. The vaccine is undergoing small phase I and phase II clinical studies. A universal coronavirus vaccine would be effective against all coronaviruses and possibly other viruses. The concept was publicly endorsed by NIAID director Anthony Fauci , virologist Jeffery K. Taubenberger , and David M. Morens. In March 2022, the White House released the "National COVID ‑ 19 Preparedness Plan", which recommended accelerating the development of a universal coronavirus vaccine. One attempt at such a vaccine is being developed at the Walter Reed Army Institute of Research . It uses a spike ferritin-based nanoparticle (SpFN). This vaccine began a Phase I clinical trial in April 2022. Another strategy is to attach vaccine fragments from multiple strains to a nanoparticle scaffold. One theory is that a broader range of strains can be vaccinated against by targeting the receptor-binding domain, rather than the whole spike protein . As of September 2020 [ update ] , eleven of the vaccine candidates in clinical development use adjuvants to enhance immunogenicity. An immunological adjuvant is a substance formulated with a vaccine to elevate the immune response to an antigen , such as the COVID ‑ 19 virus or influenza virus. Specifically, an adjuvant may be used in formulating a COVID ‑ 19 vaccine candidate to boost its immunogenicity and efficacy to reduce or prevent COVID ‑ 19 infection in vaccinated individuals. Adjuvants used in COVID ‑ 19 vaccine formulation may be particularly effective for technologies using the inactivated COVID ‑ 19 virus and recombinant protein-based or vector-based vaccines. Aluminum salts, known as " alum ", were the first adjuvant used for licensed vaccines and are the adjuvant of choice in some 80% of adjuvanted vaccines. The alum adjuvant initiates diverse molecular and cellular mechanisms to enhance immunogenicity, including the release of proinflammatory cytokines. Since January 2020, vaccine development has been expedited via unprecedented collaboration in the multinational pharmaceutical industry and between governments. Multiple steps along the entire development path are evaluated, including: the level of acceptable toxicity of the vaccine (its safety), targeting vulnerable populations, the need for vaccine efficacy breakthroughs, the duration of vaccination protection, special delivery systems (such as oral or nasal, rather than by injection), dose regimen, stability and storage characteristics, emergency use authorization before formal licensing, optimal manufacturing for scaling to billions of doses, and dissemination of the licensed vaccine. There have been several unique challenges with COVID ‑ 19 vaccine development. Public health programs [ who? ] have been described as "[a] race to vaccinate individuals" with the early wave vaccines. Timelines for conducting clinical research – normally a sequential process requiring years – are being compressed into safety, efficacy, and dosing trials running simultaneously over months, potentially compromising safety assurance. For example, Chinese vaccine developers and the Chinese Center for Disease Control and Prevention began their efforts in January 2020, and by March they were pursuing numerous candidates on short timelines. The rapid development and urgency of producing a vaccine for the COVID ‑ 19 pandemic were expected to increase the risks and failure rate of delivering a safe, effective vaccine. Additionally, research at universities is obstructed by physical distancing and the closing of laboratories. Vaccines must progress through several phases of clinical trials to test for safety, immunogenicity , effectiveness, dose levels, and adverse effects of the candidate vaccine. Vaccine developers have to invest resources internationally to find enough participants for Phase II–III clinical trials when the virus has proved to be a " moving target " of changing transmission rates across and within countries, forcing companies to compete for trial participants. Clinical trial organizers may also encounter people unwilling to be vaccinated due to vaccine hesitancy or disbelief in the science of the vaccine technology and its ability to prevent infection. As new vaccines are developed during the COVID ‑ 19 pandemic, licensure of COVID ‑ 19 vaccine candidates [ who? ] requires submission of a full dossier of information on development and manufacturing quality. Internationally, the Access to COVID‑19 Tools Accelerator is a G20 and World Health Organization (WHO) initiative announced in April 2020. It is a cross-discipline support structure to enable partners to share resources and knowledge. It comprises four pillars, each managed by two to three collaborating partners: Vaccines (also called " COVAX "), Diagnostics, Therapeutics, and Health Systems Connector. The WHO's April 2020 "R&D Blueprint (for the) novel Coronavirus" documented a "large, international, multi-site, individually randomized controlled clinical trial" to allow "the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3–6 months of it being made available for the trial." The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials and determine harmonized Phase III protocols for all vaccines achieving the pivotal trial stage. National governments have also been involved in vaccine development. Canada announced funding for 96 projects for the development and production of vaccines at Canadian companies and universities, with plans to establish a "vaccine bank" that could be used if another coronavirus outbreak occurs, support clinical trials, and develop manufacturing and supply chains for vaccines. China provided low-rate loans to one vaccine developer through its central bank and "quickly made land available for the company" to build production plants. Three Chinese vaccine companies and research institutes are supported by the government for financing research, conducting clinical trials, and manufacturing. The United Kingdom government formed a COVID ‑ 19 vaccine task force in April 2020 to stimulate local efforts for accelerated development of a vaccine through collaborations between industries, universities, and government agencies. The UK's Vaccine Taskforce contributed to every phase of development, from research to manufacturing. In the United States, the Biomedical Advanced Research and Development Authority (BARDA), a federal agency funding disease-fighting technology, announced investments to support American COVID ‑ 19 vaccine development and the manufacturing of the most promising candidates. In May 2020, the government announced funding for a fast-track program called Operation Warp Speed . By March 2021, BARDA had funded an estimated $19.3 billion in COVID ‑ 19 vaccine development. Large pharmaceutical companies with experience in making vaccines at scale, including Johnson & Johnson , AstraZeneca , and GlaxoSmithKline (GSK), formed alliances with biotechnology companies, governments, and universities to accelerate progress toward effective vaccines. There have been several unique challenges with COVID ‑ 19 vaccine development. Public health programs [ who? ] have been described as "[a] race to vaccinate individuals" with the early wave vaccines. Timelines for conducting clinical research – normally a sequential process requiring years – are being compressed into safety, efficacy, and dosing trials running simultaneously over months, potentially compromising safety assurance. For example, Chinese vaccine developers and the Chinese Center for Disease Control and Prevention began their efforts in January 2020, and by March they were pursuing numerous candidates on short timelines. The rapid development and urgency of producing a vaccine for the COVID ‑ 19 pandemic were expected to increase the risks and failure rate of delivering a safe, effective vaccine. Additionally, research at universities is obstructed by physical distancing and the closing of laboratories. Vaccines must progress through several phases of clinical trials to test for safety, immunogenicity , effectiveness, dose levels, and adverse effects of the candidate vaccine. Vaccine developers have to invest resources internationally to find enough participants for Phase II–III clinical trials when the virus has proved to be a " moving target " of changing transmission rates across and within countries, forcing companies to compete for trial participants. Clinical trial organizers may also encounter people unwilling to be vaccinated due to vaccine hesitancy or disbelief in the science of the vaccine technology and its ability to prevent infection. As new vaccines are developed during the COVID ‑ 19 pandemic, licensure of COVID ‑ 19 vaccine candidates [ who? ] requires submission of a full dossier of information on development and manufacturing quality. Internationally, the Access to COVID‑19 Tools Accelerator is a G20 and World Health Organization (WHO) initiative announced in April 2020. It is a cross-discipline support structure to enable partners to share resources and knowledge. It comprises four pillars, each managed by two to three collaborating partners: Vaccines (also called " COVAX "), Diagnostics, Therapeutics, and Health Systems Connector. The WHO's April 2020 "R&D Blueprint (for the) novel Coronavirus" documented a "large, international, multi-site, individually randomized controlled clinical trial" to allow "the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3–6 months of it being made available for the trial." The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials and determine harmonized Phase III protocols for all vaccines achieving the pivotal trial stage. National governments have also been involved in vaccine development. Canada announced funding for 96 projects for the development and production of vaccines at Canadian companies and universities, with plans to establish a "vaccine bank" that could be used if another coronavirus outbreak occurs, support clinical trials, and develop manufacturing and supply chains for vaccines. China provided low-rate loans to one vaccine developer through its central bank and "quickly made land available for the company" to build production plants. Three Chinese vaccine companies and research institutes are supported by the government for financing research, conducting clinical trials, and manufacturing. The United Kingdom government formed a COVID ‑ 19 vaccine task force in April 2020 to stimulate local efforts for accelerated development of a vaccine through collaborations between industries, universities, and government agencies. The UK's Vaccine Taskforce contributed to every phase of development, from research to manufacturing. In the United States, the Biomedical Advanced Research and Development Authority (BARDA), a federal agency funding disease-fighting technology, announced investments to support American COVID ‑ 19 vaccine development and the manufacturing of the most promising candidates. In May 2020, the government announced funding for a fast-track program called Operation Warp Speed . By March 2021, BARDA had funded an estimated $19.3 billion in COVID ‑ 19 vaccine development. Large pharmaceutical companies with experience in making vaccines at scale, including Johnson & Johnson , AstraZeneca , and GlaxoSmithKline (GSK), formed alliances with biotechnology companies, governments, and universities to accelerate progress toward effective vaccines. COVID-19 vaccine clinical research uses clinical research to establish the characteristics of COVID-19 vaccines. These characteristics include efficacy , effectiveness , and safety. As of November 2022 [ update ] , 40 vaccines are authorized by at least one national regulatory authority for public use: Post-vaccination embolic and thrombotic events, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), thrombosis with thrombocytopenia syndrome (TTS), vaccine-induced immune thrombocytopenia and thrombosis (VITT), or vaccine-associated thrombotic thrombocytopenia (VATT), are rare types of blood clotting syndromes that were initially observed in a number of people who had previously received the Oxford–AstraZeneca COVID‑19 vaccine (AZD1222) [lower-alpha 1] during the COVID‑19 pandemic . It was subsequently also described in the Janssen COVID‑19 vaccine (Johnson & Johnson), leading to the suspension of its use until its safety had been reassessed. On 5 May 2022 the FDA posted a bulletin limiting the use of the Janssen Vaccine to very specific cases due to further reassessment of the risks of TTS, although the FDA also stated in the same bulletin that the benefits of the vaccine outweigh the risks. Post-vaccination embolic and thrombotic events, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), thrombosis with thrombocytopenia syndrome (TTS), vaccine-induced immune thrombocytopenia and thrombosis (VITT), or vaccine-associated thrombotic thrombocytopenia (VATT), are rare types of blood clotting syndromes that were initially observed in a number of people who had previously received the Oxford–AstraZeneca COVID‑19 vaccine (AZD1222) [lower-alpha 1] during the COVID‑19 pandemic . It was subsequently also described in the Janssen COVID‑19 vaccine (Johnson & Johnson), leading to the suspension of its use until its safety had been reassessed. On 5 May 2022 the FDA posted a bulletin limiting the use of the Janssen Vaccine to very specific cases due to further reassessment of the risks of TTS, although the FDA also stated in the same bulletin that the benefits of the vaccine outweigh the risks. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19 , was isolated in late 2019. Its genetic sequence was published on 11 January 2020, triggering an urgent international response to prepare for an outbreak and hasten the development of a preventive COVID-19 vaccine. Since 2020, vaccine development has been expedited via unprecedented collaboration in the multinational pharmaceutical industry and between governments. By June 2020, tens of billions of dollars were invested by corporations, governments, international health organizations, and university research groups to develop dozens of vaccine candidates and prepare for global vaccination programs to immunize against COVID‑19 infection. According to the Coalition for Epidemic Preparedness Innovations (CEPI), the geographic distribution of COVID‑19 vaccine development shows North American entities to have about 40% of the activity, compared to 30% in Asia and Australia, 26% in Europe, and a few projects in South America and Africa. In February 2020, the World Health Organization (WHO) said it did not expect a vaccine against SARS‑CoV‑2 to become available in less than 18 months. Virologist Paul Offit commented that, in hindsight, the development of a safe and effective vaccine within 11 months was a remarkable feat. The rapidly growing infection rate of COVID‑19 worldwide during 2020 stimulated international alliances and government efforts to urgently organize resources to make multiple vaccines on shortened timelines, with four vaccine candidates entering human evaluation in March (see COVID-19 vaccine § Trial and authorization status ). On 24 June 2020, China approved the CanSino vaccine for limited use in the military and two inactivated virus vaccines for emergency use in high-risk occupations. On 11 August 2020, Russia announced the approval of its Sputnik V vaccine for emergency use, though one month later only small amounts of the vaccine had been distributed for use outside of the phase 3 trial. The Pfizer–BioNTech partnership submitted an Emergency Use Authorization (EUA) request to the U.S. Food and Drug Administration (FDA) for the mRNA vaccine BNT162b2 (active ingredient tozinameran ) on 20 November 2020. On 2 December 2020, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) gave temporary regulatory approval for the Pfizer–BioNTech vaccine , becoming the first country to approve the vaccine and the first country in the Western world to approve the use of any COVID‑19 vaccine. As of 21 December 2020, many countries and the European Union had authorized or approved the Pfizer–BioNTech COVID‑19 vaccine. Bahrain and the United Arab Emirates granted emergency marketing authorization for the Sinopharm BIBP vaccine . On 11 December 2020, the FDA granted an EUA for the Pfizer–BioNTech COVID‑19 vaccine. A week later, they granted an EUA for mRNA-1273 (active ingredient elasomeran ), the Moderna vaccine. On 31 March 2021, the Russian government announced that they had registered the first COVID‑19 vaccine for animals. Named Carnivac-Cov , it is an inactivated vaccine for carnivorous animals, including pets, aimed at preventing mutations that occur during the interspecies transmission of SARS-CoV-2. In October 2022, China began administering an oral vaccine developed by CanSino Biologics using its adenovirus model. In November 2021, the full nucleotide sequences of the AstraZeneca and Pfizer/BioNTech vaccines were released by the UK Medicines and Healthcare products Regulatory Agency in response to a freedom of information request. Evidence from vaccine use during the pandemic shows vaccination can reduce infection and is most effective at preventing severe COVID-19 symptoms and death, but is less good at preventing mild COVID-19. Efficacy wanes over time but can be maintained with boosters. In 2021, the CDC reported that unvaccinated people were 10 times more likely to be hospitalized and 11 times more likely to die than fully vaccinated people. The CDC reported that vaccine effectiveness fell from 91% against Alpha to 66% against Delta. One expert stated that "those who are infected following vaccination are still not getting sick and not dying like was happening before vaccination." By late August 2021, the Delta variant accounted for 99 percent of U.S. cases and was found to double the risk of severe illness and hospitalization for those not yet vaccinated. In November 2021, a study by the ECDC estimated that 470,000 lives over the age of 60 had been saved since the start of the vaccination roll-out in the European region. On 10 December 2021, the UK Health Security Agency reported that early data indicated a 20- to 40-fold reduction in neutralizing activity for Omicron by sera from Pfizer 2-dose vaccinees relative to earlier strains. After a booster dose (usually with an mRNA vaccine), vaccine effectiveness against symptomatic disease was at 70%–75% , and the effectiveness against severe disease was expected to be higher. According to early December 2021 CDC data, "unvaccinated adults were about 97 times more likely to die from COVID-19 than fully vaccinated people who had received boosters". A meta-analysis looking into COVID-19 vaccine differences in immunosuppressed individuals found that people with a weakened immune system are less able to produce neutralizing antibodies. For example, organ transplant recipients need three vaccines to achieve seroconversion . A study on the serologic response to mRNA vaccines among patients with lymphoma, leukemia, and myeloma found that one-quarter of patients did not produce measurable antibodies, varying by cancer type. In February 2023, a systematic review in The Lancet said that the protection afforded by infection was comparable to that from vaccination, albeit with an increased risk of severe illness and death from the disease of an initial infection. As of 2021, available evidence shows that fully vaccinated individuals and those previously infected with SARS-CoV-2 have a low risk of subsequent infection for at least six months. There is insufficient data to determine an antibody titer threshold that indicates when an individual is protected from infection. Multiple studies show that antibody titers are associated with protection at the population level, but individual protection titers remain unknown. For some populations, such as the elderly and the immunocompromised , protection levels may be reduced after both vaccination and infection. Available evidence indicates that the level of protection may not be the same for all variants of the virus . As of December 2021, there are no FDA-authorized or approved tests that providers or the public can use to determine if a person is protected from infection reliably. As of March 2022, elderly residents' protection against severe illness, hospitalization, and death in English care homes was high immediately after vaccination, but protection declined significantly in the months following vaccination. Protection among care home staff, who were younger, declined much more slowly. Regular boosters are recommended for older people, and boosters for care home residents every six months appear reasonable. The US Centers for Disease Control and Prevention (CDC) recommends a fourth dose of the Pfizer mRNA vaccine as of March 2022 [ update ] for "certain immunocompromised individuals and people over the age of 50". In contrast to other investigated prior variants, the SARS-CoV-2 Omicron variant and its BA.4/5 subvariants have evaded immunity induced by vaccines, which may lead to breakthrough infections despite recent vaccination. Nevertheless, vaccines are thought to provide protection against severe illness, hospitalizations, and deaths due to Omicron. In June 2022, Pfizer and Moderna developed bivalent vaccines to protect against the SARS-CoV-2 wild-type and the Omicron variant. The bivalent vaccines are well-tolerated and offer immunity to Omicron superior to previous mRNA vaccines. In September 2022, the United States Food and Drug Administration (FDA) authorized the bivalent vaccines for use in the US. As of 2022, fully vaccinated individuals with breakthrough infections with the SARS-CoV-2 delta (B.1.617.2) variant have a peak viral load similar to unvaccinated cases and can transmit infection in household settings. According to studies, the combination of two different COVID ‑ 19 vaccines, also called cross-vaccination or the mix-and-match method, provides protection equivalent to that of mRNA vaccines, including protection against the Delta variant . Individuals who receive the combination of two different vaccines produce strong immune responses, with side effects no worse than those caused by standard regimens. As of 2021, available evidence shows that fully vaccinated individuals and those previously infected with SARS-CoV-2 have a low risk of subsequent infection for at least six months. There is insufficient data to determine an antibody titer threshold that indicates when an individual is protected from infection. Multiple studies show that antibody titers are associated with protection at the population level, but individual protection titers remain unknown. For some populations, such as the elderly and the immunocompromised , protection levels may be reduced after both vaccination and infection. Available evidence indicates that the level of protection may not be the same for all variants of the virus . As of December 2021, there are no FDA-authorized or approved tests that providers or the public can use to determine if a person is protected from infection reliably. As of March 2022, elderly residents' protection against severe illness, hospitalization, and death in English care homes was high immediately after vaccination, but protection declined significantly in the months following vaccination. Protection among care home staff, who were younger, declined much more slowly. Regular boosters are recommended for older people, and boosters for care home residents every six months appear reasonable. The US Centers for Disease Control and Prevention (CDC) recommends a fourth dose of the Pfizer mRNA vaccine as of March 2022 [ update ] for "certain immunocompromised individuals and people over the age of 50". In contrast to other investigated prior variants, the SARS-CoV-2 Omicron variant and its BA.4/5 subvariants have evaded immunity induced by vaccines, which may lead to breakthrough infections despite recent vaccination. Nevertheless, vaccines are thought to provide protection against severe illness, hospitalizations, and deaths due to Omicron. In June 2022, Pfizer and Moderna developed bivalent vaccines to protect against the SARS-CoV-2 wild-type and the Omicron variant. The bivalent vaccines are well-tolerated and offer immunity to Omicron superior to previous mRNA vaccines. In September 2022, the United States Food and Drug Administration (FDA) authorized the bivalent vaccines for use in the US. In contrast to other investigated prior variants, the SARS-CoV-2 Omicron variant and its BA.4/5 subvariants have evaded immunity induced by vaccines, which may lead to breakthrough infections despite recent vaccination. Nevertheless, vaccines are thought to provide protection against severe illness, hospitalizations, and deaths due to Omicron. In June 2022, Pfizer and Moderna developed bivalent vaccines to protect against the SARS-CoV-2 wild-type and the Omicron variant. The bivalent vaccines are well-tolerated and offer immunity to Omicron superior to previous mRNA vaccines. In September 2022, the United States Food and Drug Administration (FDA) authorized the bivalent vaccines for use in the US. In June 2022, Pfizer and Moderna developed bivalent vaccines to protect against the SARS-CoV-2 wild-type and the Omicron variant. The bivalent vaccines are well-tolerated and offer immunity to Omicron superior to previous mRNA vaccines. In September 2022, the United States Food and Drug Administration (FDA) authorized the bivalent vaccines for use in the US. As of 2022, fully vaccinated individuals with breakthrough infections with the SARS-CoV-2 delta (B.1.617.2) variant have a peak viral load similar to unvaccinated cases and can transmit infection in household settings. According to studies, the combination of two different COVID ‑ 19 vaccines, also called cross-vaccination or the mix-and-match method, provides protection equivalent to that of mRNA vaccines, including protection against the Delta variant . Individuals who receive the combination of two different vaccines produce strong immune responses, with side effects no worse than those caused by standard regimens. For most people, the side effects, also called adverse effects , from COVID ‑ 19 vaccines are mild and can be managed at home. The adverse effects of the COVID ‑ 19 vaccination are similar to those of other vaccines, and severe adverse effects are rare. Adverse effects from the vaccine are higher than placebo, but placebo arms of vaccine trials still reported adverse effects that can be attributed to the nocebo effect . All vaccines that are administered via intramuscular injection , including COVID ‑ 19 vaccines, have side effects related to the mild trauma associated with the procedure and the introduction of a foreign substance into the body. These include soreness, redness, rash, and inflammation at the injection site. Other common side effects include fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain), all of which generally resolve without medical treatment within a few days. Like any other vaccine, some people are allergic to one or more ingredients in COVID ‑ 19 vaccines. Typical side effects are stronger and more common in younger people and in subsequent doses, and up to 20% of people report a disruptive level of side effects after the second dose of an mRNA vaccine. These side effects are less common or weaker in inactivated vaccines . COVID ‑ 19 vaccination-related enlargement of lymph nodes happens in 11.6% of those who received one dose of the vaccine and in 16% of those who received two doses. Experiments in mice show that intramuscular injections of lipid excipient nanoparticles (an inactive substance that serves as the vehicle or medium) cause particles to enter the blood plasma and many organs, with higher concentrations found in the liver and lower concentrations in the spleen, adrenal glands, and ovaries. The highest concentration of nanoparticles was found at the injection site itself. COVID ‑ 19 vaccination is safe for breastfeeding people. Temporary changes to the menstrual cycle in young women have been reported. However, these changes are "small compared with natural variation and quickly reverse." In one study, women who received both doses of a two-dose vaccine during the same menstrual cycle (an atypical situation) may see their next period begin a couple of days late. They have about twice the usual risk of a clinically significant delay (about 10% of these women, compared to about 4% of unvaccinated women). Cycle lengths return to normal after two menstrual cycles post-vaccination. Women who received doses in separate cycles had approximately the same natural variation in cycle lengths as unvaccinated women. Other temporary menstrual effects have been reported, such as heavier than normal menstrual bleeding after vaccination. Serious adverse events associated COVID ‑ 19 vaccines are generally rare but of high interest to the public. The official databases of reported adverse events include Increased public awareness of these reporting systems and the extra reporting requirements under US FDA Emergency Use Authorization rules have increased reported adverse events. Serious side effects are an ongoing area of study, and resources have been allocated to try and better understand them. Research currently indicates that the rate and type of side effects are lower-risk than infection. For example, although vaccination may trigger some side effects, the effects experienced from an infection could be worse. Neurological side effects from getting COVID ‑ 19 are hundreds of times more likely than from vaccination. Documented rare serious effects include: There are rare reports of subjective hearing changes, including tinnitus , after vaccination. Note about the table in this section: number and percentage of people who have received at least one dose of a COVID ‑ 19 vaccine (unless noted otherwise). May include vaccination of non-citizens, which can push totals beyond 100% of the local population. The table is updated daily by a bot. [note 2] As of 3 January 2024 [ update ] , 13.53 billion COVID-19 vaccine doses have been administered worldwide, with 70.6 percent of the global population having received at least one dose. While 4.19 million vaccines were then being administered daily, only 22.3 percent of people in low-income countries had received at least a first vaccine by September 2022, according to official reports from national health agencies, which are collated by Our World in Data . During a pandemic on the rapid timeline and scale of COVID-19 cases in 2020, international organizations like the World Health Organization (WHO) and Coalition for Epidemic Preparedness Innovations (CEPI), vaccine developers, governments, and industry evaluated the distribution of the eventual vaccine(s). Individual countries producing a vaccine may be persuaded to favor the highest bidder for manufacturing or provide first-class service to their own country. Experts emphasize that licensed vaccines should be available and affordable for people at the frontlines of healthcare and in most need. In April 2020, it was reported that the UK agreed to work with 20 other countries and global organizations, including France, Germany, and Italy, to find a vaccine and share the results, and that UK citizens would not get preferential access to any new COVID‑19 vaccines developed by taxpayer-funded UK universities. Several companies planned to initially manufacture a vaccine at artificially low prices , then increase prices for profitability later if annual vaccinations are needed and as countries build stock for future needs. Countries have extremely unequal access to the COVID ‑ 19 vaccine. Vaccine equity has not been achieved or even approximated. The inequity has harmed both countries with poor access and countries with good access. Nations pledged to buy doses of the COVID ‑ 19 vaccines before the doses were available. Though high-income nations represent only 14% of the global population, as of 15 November 2020, they had contracted to buy 51% of all pre-sold doses. Some high-income nations bought more doses than would be necessary to vaccinate their entire populations. In January 2021, WHO Director-General Tedros Adhanom Ghebreyesus warned of problems with equitable distribution: "More than 39 million doses of vaccine have now been administered in at least 49 higher-income countries. Just 25 doses have been given in one lowest-income country. Not 25 million; not 25 thousand; just 25." In March 2021, it was revealed that the US attempted to convince Brazil not to purchase the Sputnik V COVID ‑ 19 vaccine, fearing "Russian influence" in Latin America. Some nations involved in long-standing territorial disputes have reportedly had their access to vaccines blocked by competing nations; Palestine has accused Israel of blocking vaccine delivery to Gaza , while Taiwan has suggested that China has hampered its efforts to procure vaccine doses. A single dose of the COVID ‑ 19 vaccines by AstraZeneca would cost 47 Egyptian pounds (EGP), and the authorities are selling them for between 100 and 200 EGP. A report by the Carnegie Endowment for International Peace cited the poverty rate in Egypt as around 29.7 percent, which constitutes approximately 30.5 million people, and claimed that about 15 million Egyptians would be unable to gain access to the luxury of vaccination. A human rights lawyer, Khaled Ali, launched a lawsuit against the government, forcing them to provide vaccinations free of charge to all members of the public. According to immunologist Anthony Fauci , mutant strains of the virus and limited vaccine distribution pose continuing risks, and he said, "we have to get the entire world vaccinated, not just our own country." Edward Bergmark and Arick Wierson are calling for a global vaccination effort and wrote that the wealthier nations' "me-first" mentality could ultimately backfire because the spread of the virus in poorer countries would lead to more variants, against which the vaccines could be less effective. In March 2021, the United States, Britain, European Union member states, and some other members of the World Trade Organization (WTO) blocked a push by more than eighty developing countries to waive COVID ‑ 19 vaccine patent rights in an effort to boost production of vaccines for poor nations. On 5 May 2021, the US government under President Joe Biden announced that it supports waiving intellectual property protections for COVID ‑ 19 vaccines. The Members of the European Parliament have backed a motion demanding the temporary lifting of intellectual property rights for COVID ‑ 19 vaccines. In a meeting in April 2021, the World Health Organization's emergency committee addressed concerns of persistent inequity in global vaccine distribution. Although 9 percent of the world's population lives in the 29 poorest countries, these countries had received only 0.3% of all vaccines administered as of May 2021. In March 2021, Brazilian journalism agency Agência Pública reported that the country vaccinated about twice as many people who declare themselves white than black and noted that mortality from COVID ‑ 19 is higher in the black population. In May 2021, UNICEF made an urgent appeal to industrialized nations to pool their excess COVID ‑ 19 vaccine capacity to make up for a 125-million-dose gap in the COVAX program. The program mostly relied on the Oxford–AstraZeneca COVID‑19 vaccine produced by the Serum Institute of India , which faced serious supply problems due to increased domestic vaccine needs in India from March to June 2021. Only a limited amount of vaccines can be distributed efficiently, and the shortfall of vaccines in South America and parts of Asia is due to a lack of expedient donations by richer nations. International aid organizations have pointed at Nepal, Sri Lanka, and the Maldives, as well as Argentina, Brazil, and some parts of the Caribbean, as problem areas where vaccines are in short supply. In mid-May 2021, UNICEF was also critical of the fact that most proposed donations of Moderna and Pfizer vaccines were not slated for delivery until the second half of 2021 or early in 2022. In July 2021, the heads of the World Bank Group, the International Monetary Fund, the World Health Organization, and the World Trade Organization said in a joint statement: "As many countries are struggling with new variants and a third wave of COVID ‑ 19 infections, accelerating access to vaccines becomes even more critical to ending the pandemic everywhere and achieving broad-based growth. We are deeply concerned about the limited vaccines, therapeutics, diagnostics, and support for deliveries available to developing countries." In July 2021, The BMJ reported that countries had thrown out over 250,000 vaccine doses as supply exceeded demand and strict laws prevented the sharing of vaccines. A survey by The New York Times found that over a million doses of vaccine had been thrown away in ten U.S. states because federal regulations prohibit recalling them, preventing their redistribution abroad. Furthermore, doses donated close to expiration often cannot be administered quickly enough by recipient countries and end up having to be discarded. To help overcome this problem, the Prime Minister of India, Narendra Modi , announced that they would make their digital vaccination management platform, CoWIN , open to the global community. He also announced that India would also release the source code for the contact tracing app Aarogya Setu for developers around the world. Around 142 countries, including Afghanistan, Bangladesh, Bhutan, the Maldives, Guyana, Antigua and Barbuda, St. Kitts and Nevis, and Zambia, expressed their interest in the application for COVID management. Amnesty International and Oxfam International have criticized the support of vaccine monopolies by the governments of producing countries, noting that this is dramatically increasing the dose price by five times and often much more, creating an economic barrier to access for poor countries. Médecins Sans Frontières (Doctors without Borders) has also criticized vaccine monopolies and repeatedly called for their suspension, supporting the TRIPS waiver . The waiver was first proposed in October 2020 and has support from most countries, but was delayed by opposition from the EU (especially Germany; major EU countries such as France, Italy, and Spain support the exemption), the UK, Norway, and Switzerland, among others. MSF called for a Day of Action in September 2021 to put pressure on the WTO Minister's meeting in November, which was expected to discuss the TRIPS IP waiver. In August 2021, to reduce unequal distribution between rich and poor countries, the WHO called for a moratorium on booster doses at least until the end of September. However, in August, the United States government announced plans to offer booster doses eight months after the initial course to the general population, starting with priority groups. Before the announcement, the WHO harshly criticized this type of decision, citing the lack of evidence for the need for boosters, except for patients with specific conditions. At this time, vaccine coverage of at least one dose was 58% in high-income countries and only 1.3% in low-income countries, and 1.14 million Americans had already received an unauthorized booster dose. US officials argued that waning efficacy against mild and moderate disease might indicate reduced protection against severe disease in the coming months. Israel, France, Germany, and the United Kingdom have also started planning boosters for specific groups. In September 2021, more than 140 former world leaders and Nobel laureates, including former President of France François Hollande , former Prime Minister of the United Kingdom Gordon Brown , former Prime Minister of New Zealand Helen Clark , and Professor Joseph Stiglitz , called on the candidates to be the next German chancellor to declare themselves in favor of waiving intellectual property rules for COVID ‑ 19 vaccines and transferring vaccine technologies. In November 2021, nursing unions in 28 countries filed a formal appeal with the United Nations over the refusal of the UK, EU, Norway, Switzerland, and Singapore to temporarily waive patents for COVID ‑ 19 vaccines. During his first international trip, the President of Peru , Pedro Castillo , spoke at the seventy-sixth session of the United Nations General Assembly on 21 September 2021, proposing the creation of an international treaty signed by world leaders and pharmaceutical companies to guarantee universal vaccine access, arguing that "The battle against the pandemic has shown us the failure of the international community to cooperate under the principle of solidarity." Optimizing the societal benefit of vaccination may benefit from a strategy that is tailored to the state of the pandemic, the demographics of a country, the age of the recipients, the availability of vaccines, and the individual risk for severe disease. In the UK, the interval between prime and booster doses was extended to vaccinate as many people as early as possible. Many countries are starting to give an additional booster shot to the immunosuppressed and the elderly, and research predicts an additional benefit of personalizing vaccine doses in the setting of limited vaccine availability when a wave of virus Variants of Concern hits a country. Despite the extremely rapid development of effective mRNA and viral vector vaccines , vaccine equity has not been achieved. The World Health Organization called for 70 percent of the global population to be vaccinated by mid-2022, but as of March 2022, it was estimated that only one percent of the 10 billion doses given worldwide had been administered in low-income countries. An additional 6 billion vaccinations may be needed to fill vaccine access gaps, particularly in developing countries. Given the projected availability of newer vaccines, the development and use of whole inactivated virus (WIV) and protein-based vaccines are also recommended. Organizations such as the Developing Countries Vaccine Manufacturers Network could help to support the production of such vaccines in developing countries, with lower production costs and greater ease of deployment. While vaccines substantially reduce the probability and severity of infection, it is still possible for fully vaccinated people to contract and spread COVID ‑ 19. Public health agencies have recommended that vaccinated people continue using preventive measures (wear face masks, social distance, wash hands) to avoid infecting others, especially vulnerable people, particularly in areas with high community spread. Governments have indicated that such recommendations will be reduced as vaccination rates increase and community spread declines. Vaccine inequity damages the global economy, disrupting the global supply chain . Most vaccines were reserved for wealthy countries; as of September 2021 [ update ] , some countries have more vaccines than are needed to fully vaccinate their populations. When people are under-vaccinated, needlessly die, experience disability, and live under lockdown restrictions, they cannot supply the same goods and services. This harms the economies of under-vaccinated and over-vaccinated countries alike. Since rich countries have larger economies, rich countries may lose more money to vaccine inequity than poor ones, though the poor ones will lose a higher percentage of GDP and experience longer-term effects. High-income countries would profit an estimated US$4.80 for every $1 spent on giving vaccines to lower-income countries. The International Monetary Fund sees the vaccine divide between rich and poor nations as a serious obstacle to a global economic recovery. Vaccine inequity disproportionately affects refuge-providing states, as they tend to be poorer, and refugees and displaced people are economically more vulnerable even within those low-income states, so they have suffered more economically from vaccine inequity. Several governments agreed to shield pharmaceutical companies like Pfizer and Moderna from negligence claims related to COVID ‑ 19 vaccines (and treatments), as in previous pandemics , when governments also took on liability for such claims. In the US, these liability shields took effect on 4 February 2020, when the US Secretary of Health and Human Services, Alex Azar , published a notice of declaration under the Public Readiness and Emergency Preparedness Act (PREP Act) for medical countermeasures against COVID ‑ 19, covering "any vaccine, used to treat, diagnose, cure, prevent, or mitigate COVID ‑ 19, or the transmission of SARS-CoV-2 or a virus mutating therefrom". The declaration precludes "liability claims alleging negligence by a manufacturer in creating a vaccine, or negligence by a health care provider in prescribing the wrong dose, absent willful misconduct." In other words, absent "willful misconduct", these companies cannot be sued for money damages for any injuries that occur between 2020 and 2024 from the administration of vaccines and treatments related to COVID ‑ 19. The declaration is effective in the United States through 1 October 2024. In December 2020, the UK government granted Pfizer legal indemnity for its COVID ‑ 19 vaccine. In the European Union, the COVID ‑ 19 vaccines were granted a conditional marketing authorization, which does not exempt manufacturers from civil and administrative liability claims. The EU conditional marketing authorizations were changed to standard authorizations in September 2022. While the purchasing contracts with vaccine manufacturers remain secret, they do not contain liability exemptions, even for side effects not known at the time of licensure. The Bureau of Investigative Journalism , a nonprofit news organization, reported in an investigation that unnamed officials in some countries, such as Argentina and Brazil, said that Pfizer demanded guarantees against costs of legal cases due to adverse effects in the form of liability waivers and sovereign assets such as federal bank reserves, embassy buildings, or military bases, going beyond what was expected from other countries, such as the US. During the pandemic parliamentary inquiry in Brazil , Pfizer's representative said that its terms for Brazil are the same as for all other countries with which it has signed deals. On 13 December 2022, the governor of Florida, Ron DeSantis , said that he would petition the state supreme court to convene a grand jury to investigate possible violations in respect to COVID ‑ 19 vaccines, and declared that his government would be able to get "the data whether they [the companies] want to give it or not". In June 2021, a report revealed that the UB-612 vaccine, developed by the US-based Covaxx, was a for-profit venture initiated by Blackwater founder Erik Prince . In a series of text messages to Paul Behrends, the close associate recruited for the Covaxx project, Prince described the profit-making possibilities of selling the COVID ‑ 19 vaccines. Covaxx provided no data from the clinical trials on safety or efficacy it conducted in Taiwan. The responsibility of creating distribution networks was assigned to an Abu Dhabi-based entity, which was mentioned as "Windward Capital" on the Covaxx letterhead but was actually Windward Holdings. The firm's sole shareholder, who handled "professional, scientific and technical activities", was Erik Prince. In March 2021, Covaxx raised $1.35 billion in a private placement. Anti-vaccination activists and other people in many countries have spread a variety of unfounded conspiracy theories and other misinformation about COVID-19 vaccines based on misunderstood or misrepresented science, religion, and law. These have included exaggerated claims about side effects, misrepresentations about how the immune system works and when and how COVID-19 vaccines are made, a story about COVID-19 being spread by 5G , and other false or distorted information. This misinformation has proliferated and may have made many people averse to vaccination. This has led to governments and private organizations around the world introducing measures to incentivize or coerce vaccination, such as lotteries, mandates, and free entry to events, which has in turn led to further misinformation about the legality and effect of these measures themselves. Note about the table in this section: number and percentage of people who have received at least one dose of a COVID ‑ 19 vaccine (unless noted otherwise). May include vaccination of non-citizens, which can push totals beyond 100% of the local population. The table is updated daily by a bot. [note 2] As of 3 January 2024 [ update ] , 13.53 billion COVID-19 vaccine doses have been administered worldwide, with 70.6 percent of the global population having received at least one dose. While 4.19 million vaccines were then being administered daily, only 22.3 percent of people in low-income countries had received at least a first vaccine by September 2022, according to official reports from national health agencies, which are collated by Our World in Data . During a pandemic on the rapid timeline and scale of COVID-19 cases in 2020, international organizations like the World Health Organization (WHO) and Coalition for Epidemic Preparedness Innovations (CEPI), vaccine developers, governments, and industry evaluated the distribution of the eventual vaccine(s). Individual countries producing a vaccine may be persuaded to favor the highest bidder for manufacturing or provide first-class service to their own country. Experts emphasize that licensed vaccines should be available and affordable for people at the frontlines of healthcare and in most need. In April 2020, it was reported that the UK agreed to work with 20 other countries and global organizations, including France, Germany, and Italy, to find a vaccine and share the results, and that UK citizens would not get preferential access to any new COVID‑19 vaccines developed by taxpayer-funded UK universities. Several companies planned to initially manufacture a vaccine at artificially low prices , then increase prices for profitability later if annual vaccinations are needed and as countries build stock for future needs. Countries have extremely unequal access to the COVID ‑ 19 vaccine. Vaccine equity has not been achieved or even approximated. The inequity has harmed both countries with poor access and countries with good access. Nations pledged to buy doses of the COVID ‑ 19 vaccines before the doses were available. Though high-income nations represent only 14% of the global population, as of 15 November 2020, they had contracted to buy 51% of all pre-sold doses. Some high-income nations bought more doses than would be necessary to vaccinate their entire populations. In January 2021, WHO Director-General Tedros Adhanom Ghebreyesus warned of problems with equitable distribution: "More than 39 million doses of vaccine have now been administered in at least 49 higher-income countries. Just 25 doses have been given in one lowest-income country. Not 25 million; not 25 thousand; just 25." In March 2021, it was revealed that the US attempted to convince Brazil not to purchase the Sputnik V COVID ‑ 19 vaccine, fearing "Russian influence" in Latin America. Some nations involved in long-standing territorial disputes have reportedly had their access to vaccines blocked by competing nations; Palestine has accused Israel of blocking vaccine delivery to Gaza , while Taiwan has suggested that China has hampered its efforts to procure vaccine doses. A single dose of the COVID ‑ 19 vaccines by AstraZeneca would cost 47 Egyptian pounds (EGP), and the authorities are selling them for between 100 and 200 EGP. A report by the Carnegie Endowment for International Peace cited the poverty rate in Egypt as around 29.7 percent, which constitutes approximately 30.5 million people, and claimed that about 15 million Egyptians would be unable to gain access to the luxury of vaccination. A human rights lawyer, Khaled Ali, launched a lawsuit against the government, forcing them to provide vaccinations free of charge to all members of the public. According to immunologist Anthony Fauci , mutant strains of the virus and limited vaccine distribution pose continuing risks, and he said, "we have to get the entire world vaccinated, not just our own country." Edward Bergmark and Arick Wierson are calling for a global vaccination effort and wrote that the wealthier nations' "me-first" mentality could ultimately backfire because the spread of the virus in poorer countries would lead to more variants, against which the vaccines could be less effective. In March 2021, the United States, Britain, European Union member states, and some other members of the World Trade Organization (WTO) blocked a push by more than eighty developing countries to waive COVID ‑ 19 vaccine patent rights in an effort to boost production of vaccines for poor nations. On 5 May 2021, the US government under President Joe Biden announced that it supports waiving intellectual property protections for COVID ‑ 19 vaccines. The Members of the European Parliament have backed a motion demanding the temporary lifting of intellectual property rights for COVID ‑ 19 vaccines. In a meeting in April 2021, the World Health Organization's emergency committee addressed concerns of persistent inequity in global vaccine distribution. Although 9 percent of the world's population lives in the 29 poorest countries, these countries had received only 0.3% of all vaccines administered as of May 2021. In March 2021, Brazilian journalism agency Agência Pública reported that the country vaccinated about twice as many people who declare themselves white than black and noted that mortality from COVID ‑ 19 is higher in the black population. In May 2021, UNICEF made an urgent appeal to industrialized nations to pool their excess COVID ‑ 19 vaccine capacity to make up for a 125-million-dose gap in the COVAX program. The program mostly relied on the Oxford–AstraZeneca COVID‑19 vaccine produced by the Serum Institute of India , which faced serious supply problems due to increased domestic vaccine needs in India from March to June 2021. Only a limited amount of vaccines can be distributed efficiently, and the shortfall of vaccines in South America and parts of Asia is due to a lack of expedient donations by richer nations. International aid organizations have pointed at Nepal, Sri Lanka, and the Maldives, as well as Argentina, Brazil, and some parts of the Caribbean, as problem areas where vaccines are in short supply. In mid-May 2021, UNICEF was also critical of the fact that most proposed donations of Moderna and Pfizer vaccines were not slated for delivery until the second half of 2021 or early in 2022. In July 2021, the heads of the World Bank Group, the International Monetary Fund, the World Health Organization, and the World Trade Organization said in a joint statement: "As many countries are struggling with new variants and a third wave of COVID ‑ 19 infections, accelerating access to vaccines becomes even more critical to ending the pandemic everywhere and achieving broad-based growth. We are deeply concerned about the limited vaccines, therapeutics, diagnostics, and support for deliveries available to developing countries." In July 2021, The BMJ reported that countries had thrown out over 250,000 vaccine doses as supply exceeded demand and strict laws prevented the sharing of vaccines. A survey by The New York Times found that over a million doses of vaccine had been thrown away in ten U.S. states because federal regulations prohibit recalling them, preventing their redistribution abroad. Furthermore, doses donated close to expiration often cannot be administered quickly enough by recipient countries and end up having to be discarded. To help overcome this problem, the Prime Minister of India, Narendra Modi , announced that they would make their digital vaccination management platform, CoWIN , open to the global community. He also announced that India would also release the source code for the contact tracing app Aarogya Setu for developers around the world. Around 142 countries, including Afghanistan, Bangladesh, Bhutan, the Maldives, Guyana, Antigua and Barbuda, St. Kitts and Nevis, and Zambia, expressed their interest in the application for COVID management. Amnesty International and Oxfam International have criticized the support of vaccine monopolies by the governments of producing countries, noting that this is dramatically increasing the dose price by five times and often much more, creating an economic barrier to access for poor countries. Médecins Sans Frontières (Doctors without Borders) has also criticized vaccine monopolies and repeatedly called for their suspension, supporting the TRIPS waiver . The waiver was first proposed in October 2020 and has support from most countries, but was delayed by opposition from the EU (especially Germany; major EU countries such as France, Italy, and Spain support the exemption), the UK, Norway, and Switzerland, among others. MSF called for a Day of Action in September 2021 to put pressure on the WTO Minister's meeting in November, which was expected to discuss the TRIPS IP waiver. In August 2021, to reduce unequal distribution between rich and poor countries, the WHO called for a moratorium on booster doses at least until the end of September. However, in August, the United States government announced plans to offer booster doses eight months after the initial course to the general population, starting with priority groups. Before the announcement, the WHO harshly criticized this type of decision, citing the lack of evidence for the need for boosters, except for patients with specific conditions. At this time, vaccine coverage of at least one dose was 58% in high-income countries and only 1.3% in low-income countries, and 1.14 million Americans had already received an unauthorized booster dose. US officials argued that waning efficacy against mild and moderate disease might indicate reduced protection against severe disease in the coming months. Israel, France, Germany, and the United Kingdom have also started planning boosters for specific groups. In September 2021, more than 140 former world leaders and Nobel laureates, including former President of France François Hollande , former Prime Minister of the United Kingdom Gordon Brown , former Prime Minister of New Zealand Helen Clark , and Professor Joseph Stiglitz , called on the candidates to be the next German chancellor to declare themselves in favor of waiving intellectual property rules for COVID ‑ 19 vaccines and transferring vaccine technologies. In November 2021, nursing unions in 28 countries filed a formal appeal with the United Nations over the refusal of the UK, EU, Norway, Switzerland, and Singapore to temporarily waive patents for COVID ‑ 19 vaccines. During his first international trip, the President of Peru , Pedro Castillo , spoke at the seventy-sixth session of the United Nations General Assembly on 21 September 2021, proposing the creation of an international treaty signed by world leaders and pharmaceutical companies to guarantee universal vaccine access, arguing that "The battle against the pandemic has shown us the failure of the international community to cooperate under the principle of solidarity." Optimizing the societal benefit of vaccination may benefit from a strategy that is tailored to the state of the pandemic, the demographics of a country, the age of the recipients, the availability of vaccines, and the individual risk for severe disease. In the UK, the interval between prime and booster doses was extended to vaccinate as many people as early as possible. Many countries are starting to give an additional booster shot to the immunosuppressed and the elderly, and research predicts an additional benefit of personalizing vaccine doses in the setting of limited vaccine availability when a wave of virus Variants of Concern hits a country. Despite the extremely rapid development of effective mRNA and viral vector vaccines , vaccine equity has not been achieved. The World Health Organization called for 70 percent of the global population to be vaccinated by mid-2022, but as of March 2022, it was estimated that only one percent of the 10 billion doses given worldwide had been administered in low-income countries. An additional 6 billion vaccinations may be needed to fill vaccine access gaps, particularly in developing countries. Given the projected availability of newer vaccines, the development and use of whole inactivated virus (WIV) and protein-based vaccines are also recommended. Organizations such as the Developing Countries Vaccine Manufacturers Network could help to support the production of such vaccines in developing countries, with lower production costs and greater ease of deployment. While vaccines substantially reduce the probability and severity of infection, it is still possible for fully vaccinated people to contract and spread COVID ‑ 19. Public health agencies have recommended that vaccinated people continue using preventive measures (wear face masks, social distance, wash hands) to avoid infecting others, especially vulnerable people, particularly in areas with high community spread. Governments have indicated that such recommendations will be reduced as vaccination rates increase and community spread declines. Vaccine inequity damages the global economy, disrupting the global supply chain . Most vaccines were reserved for wealthy countries; as of September 2021 [ update ] , some countries have more vaccines than are needed to fully vaccinate their populations. When people are under-vaccinated, needlessly die, experience disability, and live under lockdown restrictions, they cannot supply the same goods and services. This harms the economies of under-vaccinated and over-vaccinated countries alike. Since rich countries have larger economies, rich countries may lose more money to vaccine inequity than poor ones, though the poor ones will lose a higher percentage of GDP and experience longer-term effects. High-income countries would profit an estimated US$4.80 for every $1 spent on giving vaccines to lower-income countries. The International Monetary Fund sees the vaccine divide between rich and poor nations as a serious obstacle to a global economic recovery. Vaccine inequity disproportionately affects refuge-providing states, as they tend to be poorer, and refugees and displaced people are economically more vulnerable even within those low-income states, so they have suffered more economically from vaccine inequity. Vaccine inequity damages the global economy, disrupting the global supply chain . Most vaccines were reserved for wealthy countries; as of September 2021 [ update ] , some countries have more vaccines than are needed to fully vaccinate their populations. When people are under-vaccinated, needlessly die, experience disability, and live under lockdown restrictions, they cannot supply the same goods and services. This harms the economies of under-vaccinated and over-vaccinated countries alike. Since rich countries have larger economies, rich countries may lose more money to vaccine inequity than poor ones, though the poor ones will lose a higher percentage of GDP and experience longer-term effects. High-income countries would profit an estimated US$4.80 for every $1 spent on giving vaccines to lower-income countries. The International Monetary Fund sees the vaccine divide between rich and poor nations as a serious obstacle to a global economic recovery. Vaccine inequity disproportionately affects refuge-providing states, as they tend to be poorer, and refugees and displaced people are economically more vulnerable even within those low-income states, so they have suffered more economically from vaccine inequity. Several governments agreed to shield pharmaceutical companies like Pfizer and Moderna from negligence claims related to COVID ‑ 19 vaccines (and treatments), as in previous pandemics , when governments also took on liability for such claims. In the US, these liability shields took effect on 4 February 2020, when the US Secretary of Health and Human Services, Alex Azar , published a notice of declaration under the Public Readiness and Emergency Preparedness Act (PREP Act) for medical countermeasures against COVID ‑ 19, covering "any vaccine, used to treat, diagnose, cure, prevent, or mitigate COVID ‑ 19, or the transmission of SARS-CoV-2 or a virus mutating therefrom". The declaration precludes "liability claims alleging negligence by a manufacturer in creating a vaccine, or negligence by a health care provider in prescribing the wrong dose, absent willful misconduct." In other words, absent "willful misconduct", these companies cannot be sued for money damages for any injuries that occur between 2020 and 2024 from the administration of vaccines and treatments related to COVID ‑ 19. The declaration is effective in the United States through 1 October 2024. In December 2020, the UK government granted Pfizer legal indemnity for its COVID ‑ 19 vaccine. In the European Union, the COVID ‑ 19 vaccines were granted a conditional marketing authorization, which does not exempt manufacturers from civil and administrative liability claims. The EU conditional marketing authorizations were changed to standard authorizations in September 2022. While the purchasing contracts with vaccine manufacturers remain secret, they do not contain liability exemptions, even for side effects not known at the time of licensure. The Bureau of Investigative Journalism , a nonprofit news organization, reported in an investigation that unnamed officials in some countries, such as Argentina and Brazil, said that Pfizer demanded guarantees against costs of legal cases due to adverse effects in the form of liability waivers and sovereign assets such as federal bank reserves, embassy buildings, or military bases, going beyond what was expected from other countries, such as the US. During the pandemic parliamentary inquiry in Brazil , Pfizer's representative said that its terms for Brazil are the same as for all other countries with which it has signed deals. On 13 December 2022, the governor of Florida, Ron DeSantis , said that he would petition the state supreme court to convene a grand jury to investigate possible violations in respect to COVID ‑ 19 vaccines, and declared that his government would be able to get "the data whether they [the companies] want to give it or not". In June 2021, a report revealed that the UB-612 vaccine, developed by the US-based Covaxx, was a for-profit venture initiated by Blackwater founder Erik Prince . In a series of text messages to Paul Behrends, the close associate recruited for the Covaxx project, Prince described the profit-making possibilities of selling the COVID ‑ 19 vaccines. Covaxx provided no data from the clinical trials on safety or efficacy it conducted in Taiwan. The responsibility of creating distribution networks was assigned to an Abu Dhabi-based entity, which was mentioned as "Windward Capital" on the Covaxx letterhead but was actually Windward Holdings. The firm's sole shareholder, who handled "professional, scientific and technical activities", was Erik Prince. In March 2021, Covaxx raised $1.35 billion in a private placement. Anti-vaccination activists and other people in many countries have spread a variety of unfounded conspiracy theories and other misinformation about COVID-19 vaccines based on misunderstood or misrepresented science, religion, and law. These have included exaggerated claims about side effects, misrepresentations about how the immune system works and when and how COVID-19 vaccines are made, a story about COVID-19 being spread by 5G , and other false or distorted information. This misinformation has proliferated and may have made many people averse to vaccination. This has led to governments and private organizations around the world introducing measures to incentivize or coerce vaccination, such as lotteries, mandates, and free entry to events, which has in turn led to further misinformation about the legality and effect of these measures themselves.

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Chikungunya

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Petechia

pɪˈtiːkɪə A petechia ( / p ɪ ˈ t iː k i ə / ; pl. : petechiae ) is a small red or purple spot (≤4 mm in diameter) that can appear on the skin , conjunctiva , retina , and mucous membranes which is caused by haemorrhage of capillaries. The word is derived from Italian petecchia , 'freckle,' of obscure origin. It refers to one of the three descriptive types of hematoma differentiated by size, the other two being ecchymosis (>1cm in diameter) and purpura (4-10mm in diameter). The term is typically used in the plural (petechiae), since a single petechia is seldom noticed or significant.The most common cause of petechiae is through physical trauma such as a hard bout of coughing, holding breath, vomiting, or crying, which can result in facial petechiae, especially around the eyes. Excessive scratching and friction, especially on thin and poorly circulated parts of the body may also cause petechiae. Such instances are generally considered harmless and usually disappear within a few days, but depending on severity and frequency may be indicative of an underlying medical condition.The most common cause of petechiae is through physical trauma such as a hard bout of coughing, holding breath, vomiting, or crying, which can result in facial petechiae, especially around the eyes. Excessive scratching and friction, especially on thin and poorly circulated parts of the body may also cause petechiae. Such instances are generally considered harmless and usually disappear within a few days, but depending on severity and frequency may be indicative of an underlying medical condition.Petechiae on the face and conjunctiva (eyes) are unrelated to asphyxiation or hypoxia . Despite this, petechiae are used by police investigators in determining whether strangulation has been part of an attack. The documentation of the presence of petechiae on a victim can help police investigators prove the case. Petechiae resulting from strangulation can be relatively tiny and light in color to very bright and pronounced. Petechiae may be seen on the face, in the whites of the eyes or on the inside of the eyelids.

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Chikungunya

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Yellow fever

Yellow fever is a viral disease of typically short duration . In most cases, symptoms include fever , chills , loss of appetite , nausea , muscle pains—particularly in the back—and headaches . Symptoms typically improve within five days. In about 15% of people, within a day of improving the fever comes back, abdominal pain occurs, and liver damage begins causing yellow skin . If this occurs, the risk of bleeding and kidney problems is increased. The disease is caused by the yellow fever virus and is spread by the bite of an infected mosquito . It infects humans, other primates , and several types of mosquitoes. In cities, it is spread primarily by Aedes aegypti , a type of mosquito found throughout the tropics and subtropics . The virus is an RNA virus of the genus Flavivirus . The disease may be difficult to tell apart from other illnesses, especially in the early stages. To confirm a suspected case, blood-sample testing with a polymerase chain reaction is required. A safe and effective vaccine against yellow fever exists, and some countries require vaccinations for travelers. Other efforts to prevent infection include reducing the population of the transmitting mosquitoes. In areas where yellow fever is common, early diagnosis of cases and immunization of large parts of the population are important to prevent outbreaks . Once a person is infected, management is symptomatic; no specific measures are effective against the virus. Death occurs in up to half of those who get severe disease. In 2013, yellow fever was estimated to have caused 130,000 severe infections and 78,000 deaths in Africa. Approximately 90 percent of an estimated 200,000 cases of yellow fever per year occur in Africa. Nearly a billion people live in an area of the world where the disease is common. It is common in tropical areas of the continents of South America and Africa, but not in Asia. Since the 1980s, the number of cases of yellow fever has been increasing. This is believed to be due to fewer people being immune, more people living in cities, people moving frequently, and changing climate increasing the habitat for mosquitoes. The disease originated in Africa and spread to the Americas starting in the 17th century with the European trafficking of enslaved Africans from sub-Saharan Africa. Since the 17th century, several major outbreaks of the disease have occurred in the Americas, Africa, and Europe. In the 18th and 19th centuries, yellow fever was considered one of the most dangerous infectious diseases ; numerous epidemics swept through major cities of the US and in other parts of the world. In 1927, yellow fever virus became the first human virus to be isolated. Yellow fever begins after an incubation period of three to six days. Most cases cause only mild infection with fever, headache, chills, back pain, fatigue, loss of appetite, muscle pain, nausea, and vomiting. In these cases, the infection lasts only three to six days. But in 15% of cases, people enter a second, toxic phase of the disease characterized by recurring fever, this time accompanied by jaundice due to liver damage , as well as abdominal pain . Bleeding in the mouth, nose, eyes, and the gastrointestinal tract cause vomit containing blood , hence one of the names in Spanish for yellow fever, vómito negro ("black vomit"). There may also be kidney failure, hiccups, and delirium. Among those who develop jaundice, the fatality rate is 20 to 50%, while the overall fatality rate is about 3 to 7.5%. Severe cases may have a mortality rate greater than 50%. Surviving the infection provides lifelong immunity , and normally results in no permanent organ damage. Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time. Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time. {| class="infobox biota" style="text-align: left; width: 200px; font-size: 100%" |- ! Yellow fever virus |- | |- | Flavivirus structure and genome |- |- |- |- ! Virus classification |- |(unranked): | Virus |- | Realm : | Riboviria |- |Kingdom: | Orthornavirae |- |Phylum: | Kitrinoviricota |- |Class: | Flasuviricetes |- |Order: | Amarillovirales |- |Family: | Flaviviridae |- |Genus: | Flavivirus |- | Species: | |- |- |- |- |- |- |- |- |- |- |- |- |- |- |- |} Yellow fever is caused by Yellow fever virus (YFV), an enveloped RNA virus 40–50 nm in width, the type species and namesake of the family Flaviviridae . It was the first illness shown to be transmissible by filtered human serum and transmitted by mosquitoes, by American doctor Walter Reed around 1900. The positive- sense , single-stranded RNA is around 10,862 nucleotides long and has a single open reading frame encoding a polyprotein . Host proteases cut this polyprotein into three structural (C, prM, E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding genes in the genome . Minimal YFV 3 ′ UTR region is required for stalling of the host 5 ′ -3 ′ exonuclease XRN1. The UTR contains PKS3 pseudoknot structure, which serves as a molecular signal to stall the exonuclease and is the only viral requirement for subgenomic flavivirus RNA (sfRNA) production. The sfRNAs are a result of incomplete degradation of the viral genome by the exonuclease and are important for viral pathogenicity. Yellow fever belongs to the group of hemorrhagic fevers . The viruses infect, amongst others, monocytes , macrophages , Schwann cells , and dendritic cells . They attach to the cell surfaces via specific receptors and are taken up by an endosomal vesicle . Inside the endosome , the decreased pH induces the fusion of the endosomal membrane with the virus envelope . The capsid enters the cytosol , decays, and releases the genome. Receptor binding, as well as membrane fusion, are catalyzed by the protein E, which changes its conformation at low pH, causing a rearrangement of the 90 homo dimers to 60 homo trimers . After entering the host cell, the viral genome is replicated in the rough endoplasmic reticulum (ER) and in the so-called vesicle packets. At first, an immature form of the virus particle is produced inside the ER, whose M-protein is not yet cleaved to its mature form, so is denoted as precursor M (prM) and forms a complex with protein E. The immature particles are processed in the Golgi apparatus by the host protein furin , which cleaves prM to M. This releases E from the complex, which can now take its place in the mature, infectious virion . Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti , but other mostly Aedes mosquitoes such as the tiger mosquito ( Aedes albopictus ) can also serve as a vector for this virus. Like other arboviruses , which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate. Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands . When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti , that is, the transmission from a female mosquito to its eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease. Three epidemiologically different infectious cycles occur in which the virus is transmitted from mosquitoes to humans or other primates. In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever , dengue fever , and chikungunya . The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America. Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent. People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors. In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa. Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs. Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti , but other mostly Aedes mosquitoes such as the tiger mosquito ( Aedes albopictus ) can also serve as a vector for this virus. Like other arboviruses , which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate. Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands . When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti , that is, the transmission from a female mosquito to its eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease. Three epidemiologically different infectious cycles occur in which the virus is transmitted from mosquitoes to humans or other primates. In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever , dengue fever , and chikungunya . The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America. Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent. People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors. In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa. Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs. After transmission from a mosquito, the viruses replicate in the lymph nodes and infect dendritic cells in particular. From there, they reach the liver and infect hepatocytes (probably indirectly via Kupffer cells ), which leads to eosinophilic degradation of these cells and to the release of cytokines . Apoptotic masses known as Councilman bodies appear in the cytoplasm of hepatocytes. Fatality may occur when cytokine storm , shock , and multiple organ failure follow. Yellow fever is most frequently a clinical diagnosis , based on symptomatology and travel history. Mild cases of the disease can only be confirmed virologically. Since mild cases of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea, and vomiting 6–10 days after leaving the affected area) is treated seriously. If yellow fever is suspected, the virus cannot be confirmed until 6–10 days following the illness. A direct confirmation can be obtained by reverse transcription polymerase chain reaction , where the genome of the virus is amplified. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma ; this can take 1–4 weeks. Serologically, an enzyme-linked immunosorbent assay during the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG titer (compared to an earlier sample) can confirm yellow fever. Together with clinical symptoms, the detection of IgM or a four-fold increase in IgG titer is considered sufficient indication for yellow fever. As these tests can cross-react with other flaviviruses, such as dengue virus , these indirect methods cannot conclusively prove yellow fever infection. Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens . Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable post mortem to confirm the cause of death. In a differential diagnosis , infections with yellow fever must be distinguished from other feverish illnesses such as malaria . Other viral hemorrhagic fevers , such as Ebola virus , Lassa virus , Marburg virus , and Junin virus , must be excluded as the cause. Personal prevention of yellow fever includes vaccination and avoidance of mosquito bites in areas where yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes and measures to control mosquitoes. Programmes for distribution of mosquito nets for use in homes produce reductions in cases of both malaria and yellow fever. Use of EPA-registered insect repellent is recommended when outdoors. Exposure for even a short time is enough for a potential mosquito bite. Long-sleeved clothing, long pants, and socks are useful for prevention. The application of larvicides to water-storage containers can help eliminate potential mosquito breeding sites. EPA-registered insecticide spray decreases the transmission of yellow fever. Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler . The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases. The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply. Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016. Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose. In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Control of the yellow fever mosquito A. aegypti is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. A. aegypti breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries. Two main strategies are employed to reduce A. aegypti populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods , which reduce the number of larvae. For many years, copepods of the genus Mesocyclops have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses. The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce Aedes populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the Anopheles mosquito that carries malaria. Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler . The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases. The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply. Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016. Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose. In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Control of the yellow fever mosquito A. aegypti is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. A. aegypti breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries. Two main strategies are employed to reduce A. aegypti populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods , which reduce the number of larvae. For many years, copepods of the genus Mesocyclops have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses. The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce Aedes populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the Anopheles mosquito that carries malaria. As with other Flavivirus infections, no cure is known for yellow fever. Hospitalization is advisable and intensive care may be necessary because of rapid deterioration in some cases. Certain acute treatment methods lack efficacy: passive immunization after the emergence of symptoms is probably without effect; ribavirin and other antiviral drugs , as well as treatment with interferons , are ineffective in yellow fever patients. Symptomatic treatment includes rehydration and pain relief with drugs such as paracetamol (acetaminophen). However, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are often avoided because of an increased risk of gastrointestinal bleeding due to their anticoagulant effects. Yellow fever is common in tropical and subtropical areas of South America and Africa. Worldwide, about 600 million people live in endemic areas. The WHO estimates 200,000 cases of yellow fever worldwide each year. About 15% of people infected with yellow fever progress to a severe form of the illness, and up to half of those will die, as there is no cure for yellow fever. An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history. Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector A. aegypti . Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years. In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvatic or jungle epizootic . Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016, spreading rapidly across several neotropical monkey species, including brown howler monkeys, which serve as a sentinel species for yellow fever. No cases had been transmitted between humans by the A. aegypti mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.) A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil , Colombia , Venezuela , and Trinidad and Tobago , while genotype II accounted for all cases in Peru . Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10 −4 substitutions/site/year, similar to that of other RNA viruses. The main vector ( A. aegypti ) also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include: But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa. An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history. Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector A. aegypti . Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years. In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvatic or jungle epizootic . Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016, spreading rapidly across several neotropical monkey species, including brown howler monkeys, which serve as a sentinel species for yellow fever. No cases had been transmitted between humans by the A. aegypti mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.) A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil , Colombia , Venezuela , and Trinidad and Tobago , while genotype II accounted for all cases in Peru . Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10 −4 substitutions/site/year, similar to that of other RNA viruses. The main vector ( A. aegypti ) also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include: But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa. The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza . This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity . The virus, as well as the vector A. aegypti, were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus Haemagogus , which is indigenous to the Americas, have been known to carry the disease. The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados . An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula , where the indigenous Mayan people called the illness xekik ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife . The first mention of the disease by the name "yellow fever" occurred in 1744. However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs. In Colonial times and during the Napoleonic Wars , the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack" . Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated. Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore , and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson , a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington . The southern city of New Orleans was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in Cartagena, Chile , in 1741; Cuba in 1762 and 1900; Santo Domingo in 1803; and Memphis, Tennessee , in 1878. In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the United States Navy as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS Macedonian left Boston and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana , had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of Savannah, Georgia , died from yellow fever. In 1858, St. Matthew's German Evangelical Lutheran Church in Charleston, South Carolina , had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 1855. The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth . In 1873, Shreveport, Louisiana , lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe. Gibraltar lost many lives to outbreaks in 1804, 1814, and 1828. Barcelona suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between France and Spain in the Pyrenees Mountains , to establish a cordon sanitaire in order to prevent the epidemic from spreading from Spain into France. Ezekiel Stone Wiggins , known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in Jacksonville, Florida , in 1888, was astrological. The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered canals , which were perhaps made to absorb carbon and prevent the disease. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease. Carlos Finlay , a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by Walter Reed , and composed of doctors James Carroll , Aristides Agramonte , and Jesse William Lazear . They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician William Gorgas applied these insights and eradicated yellow fever from Havana . He also campaigned against yellow fever during the construction of the Panama Canal . A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz , then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in favelas . During 1920–1923, the Rockefeller Foundation 's International Health Board undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the yellow fever virus in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the Nobel Prize in Physiology or Medicine . That vaccine, 17D, is still in use, although newer vaccines, based on vero cells , are in development (as of 2018). Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in Santa Cruz de la Sierra , Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in Paraguay in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely. The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza . This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity . The virus, as well as the vector A. aegypti, were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus Haemagogus , which is indigenous to the Americas, have been known to carry the disease. The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados . An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula , where the indigenous Mayan people called the illness xekik ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife . The first mention of the disease by the name "yellow fever" occurred in 1744. However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs. In Colonial times and during the Napoleonic Wars , the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack" . Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated. Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore , and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson , a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington . The southern city of New Orleans was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in Cartagena, Chile , in 1741; Cuba in 1762 and 1900; Santo Domingo in 1803; and Memphis, Tennessee , in 1878. In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the United States Navy as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS Macedonian left Boston and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana , had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of Savannah, Georgia , died from yellow fever. In 1858, St. Matthew's German Evangelical Lutheran Church in Charleston, South Carolina , had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 1855. The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth . In 1873, Shreveport, Louisiana , lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe. Gibraltar lost many lives to outbreaks in 1804, 1814, and 1828. Barcelona suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between France and Spain in the Pyrenees Mountains , to establish a cordon sanitaire in order to prevent the epidemic from spreading from Spain into France. Ezekiel Stone Wiggins , known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in Jacksonville, Florida , in 1888, was astrological. The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered canals , which were perhaps made to absorb carbon and prevent the disease. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease. Carlos Finlay , a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by Walter Reed , and composed of doctors James Carroll , Aristides Agramonte , and Jesse William Lazear . They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician William Gorgas applied these insights and eradicated yellow fever from Havana . He also campaigned against yellow fever during the construction of the Panama Canal . A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz , then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in favelas . During 1920–1923, the Rockefeller Foundation 's International Health Board undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the yellow fever virus in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the Nobel Prize in Physiology or Medicine . That vaccine, 17D, is still in use, although newer vaccines, based on vero cells , are in development (as of 2018). Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in Santa Cruz de la Sierra , Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in Paraguay in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely. In the hamster model of yellow fever, early administration of the antiviral ribavirin is an effective treatment of many pathological features of the disease. Ribavirin treatment during the first five days after virus infection improved survival rates, reduced tissue damage in the liver and spleen , prevented hepatocellular steatosis , and normalised levels of alanine aminotransferase, a liver damage marker. The mechanism of action of ribavirin in reducing liver pathology in yellow fever virus infection may be similar to its activity in treatment of hepatitis C , a related virus. Because ribavirin had failed to improve survival in a virulent rhesus model of yellow fever infection, it had been previously discounted as a possible therapy. Infection was reduced in mosquitoes with the wMel strain of Wolbachia . Yellow fever has been researched by several countries as a potential biological weapon .

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Chikungunya

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Aedes aegypti

Aedes aegypti aegypti Aedes aegypti formosus Aedes aegypti ( /ˈiːdiːz/ from Greek αηδής : "hateful" and /aɪˈdʒɛpti/ from Latin , meaning "of Egypt"), the yellow fever mosquito , is a mosquito that can spread dengue fever , chikungunya , Zika fever , Mayaro and yellow fever viruses, and other disease agents. The mosquito can be recognized by black and white markings on its legs and a marking in the form of a lyre on the upper surface of its thorax . This mosquito originated in Africa, but is now found in tropical , subtropical and temperate regions throughout the world.Aedes aegypti is a 4–7 millimetres ( 5 ⁄ 32 – 35 ⁄ 128 in) long, dark mosquito which can be recognized by white markings on its legs and a marking in the form of a lyre on the upper surface of its thorax . Females are larger than males. Microscopically females possess small palps tipped with silver or white scales, and their antennae have sparse short hairs, whereas those of males are feathery. Aedes aegypti can be confused with Aedes albopictus without a magnifying glass: the latter have a white stripe on the top of the mid thorax. Males live off fruit and only the female bites for blood, which she needs to mature her eggs. To find a host, she is attracted to chemical compounds emitted by mammals, including ammonia , carbon dioxide , lactic acid , and octenol . Scientists at The United States Department of Agriculture (USDA) Agricultural Research Service studied the specific chemical structure of octenol to better understand why this chemical attracts the mosquito to its host and found the mosquito has a preference for "right-handed" ( dextrorotatory ) octenol molecules. The preference for biting humans is dependent on expression of the odorant receptor AaegOr4 . The white eggs are laid separately into water and not together, unlike most other mosquitoes, and soon turn black. The larvae feed on bacteria, growing over a period of weeks until they reach the pupa stage. The lifespan of an adult Ae. aegypti is two to four weeks depending on conditions, but the eggs can be viable for over a year in a dry state, which allows the mosquito to re-emerge after a cold winter or dry spell. Mammalian hosts include domesticated horses , and feral and wild horses and equids more generally. As of 2009 birds were found to be the best food supply for Ae. aegypti among all taxa . Mammalian hosts include domesticated horses , and feral and wild horses and equids more generally. As of 2009 birds were found to be the best food supply for Ae. aegypti among all taxa . Aedes aegypti originated in Africa and was spread to the New World through slave trade, but is now found in tropical , subtropical and temperate regions throughout the world. Ae. aegypti ' s distribution has increased in the past two to three decades worldwide, and it is considered to be among the most widespread mosquito species. In 2016, Zika virus -capable mosquito populations have been found adapting for persistence in warm temperate climates. Such a population has been identified to exist in parts of Washington, DC , and genetic evidence suggests they survived at least the last four winters in the region. One of the study researchers noted, "...some mosquito species are finding ways to survive in normally restrictive environments by taking advantage of underground refugia". As the world's climate becomes warmer, the range of Aedes aegypti and a hardier species originating in Asia, the tiger mosquito Aedes albopictus , which can expand its range to relatively cooler climates, will inexorably spread north and south. Sadie Ryan of the University of Florida was the lead author in a 2019 study that estimated the vulnerability of naïve populations in geographic regions that currently do not harbor vectors i.e., for Zika in the Old World. Ryan's co-author, Georgetown University's Colin Carlson remarked,"Plain and simple, climate change is going to kill a lot of people." As of 2020, the Northern Territory Government Australia and the Darwin City Council have recommended tropical cities initiate rectification programs to rid their cities of potential mosquito breeding stormwater sumps. A 2019 study found that accelerating urbanization and human movement would also contribute to the spread of Aedes mosquitoes. In continental Europe, Aedes aegypti is not established but it has been found in localities close to Europe such as the Asian part of Turkey . However, a single adult female specimen was found in Marseille (Southern France) in 2018. On the basis of a genetic study and an analysis of the movements of commercial ships, the origin of the specimen could be traced as coming from Cameroon , in Central Africa. In 2007, the genome of Aedes aegypti was published, after it had been sequenced and analyzed by a consortium including scientists at The Institute for Genomic Research (now part of the J. Craig Venter Institute ), the European Bioinformatics Institute , the Broad Institute , and the University of Notre Dame . The effort in sequencing its DNA was intended to provide new avenues for research into insecticides and possible genetic modification to prevent the spread of virus. This was the second mosquito species to have its genome sequenced in full (the first was Anopheles gambiae ). The published data included the 1.38 billion base pairs containing the insect's estimated 15,419 protein -encoding genes. The sequence indicates the species diverged from Drosophila melanogaster (the common fruit fly) about 250 million years ago , and Anopheles gambiae and this species diverged about 150 million years ago . Matthews et al. , 2018 finds A. aegypti to carry a large and diverse number of transposable elements . Their analysis suggests this is common to all mosquitoes. Aedes aegypti is a vector for transmitting numerous pathogens . According to the Walter Reed Biosystematics Units as of 2022, it is associated with the following 54 viruses and 2 species of Plasmodium : Aino virus (AINOV), African horse sickness virus (AHSV), Bozo virus (BOZOV), Bussuquara virus (BSQV), Bunyamwera virus (BUNV), Catu virus (CATUV), Chikungunya virus (CHIKV), Chandipura vesiculovirus (CHPV), Cypovirus (unnamed), Cache Valley virus (CVV), Dengue virus (DENV), Eastern Equine Encephalitis virus (EEEV), Epizootic hemorrhagic disease virus (EHDV), Guaroa virus (GROV), Hart Park virus (HPV), Ilheus virus (ILHV), Irituia virus (IRIV), Israel Turkey Meningoencephalitis virus (ITV), Japanaut virus (JAPV), Joinjakaka (JOIV), Japanese encephalitis virus (JBEV), Ketapang virus (KETV), Kunjin virus (KUNV), La Crosse virus (LACV), Mayaro virus (MAYV), Marburg virus (MBGV), Marco virus (MCOV), Melao virus (MELV), Marituba virus (MTBV), Mount Elgon bat virus (MEBV), Mucambo virus (MUCV), Murray Valley Encephalitis virus (MVEV), Navarro virus (NAVV), Nepuyo virus (NEPV), Nola virus (NOLV), Ntaya virus (NTAV), Oriboca virus (ORIV), Orungo virus (ORUV), Restan virus (RESV), Rift Valley fever virus (RVFV), Semliki Forest virus (SFV), Sindbis virus (SINV), Tahyna virus (TAHV), Tsuruse virus (TSUV), Tyuleniy virus (TYUV), Venezuelan equine encephalitis virus (VEEV), Vesicular stomatitis virus (Indiana serotype), Warrego virus (WARV), West Nile virus (WNV), Wesselsbron virus (WSLV), Yaounde virus (YAOV), Yellow fever virus (YFV), Zegla virus (ZEGV), Zika virus , as well as Plasmodium gallinaceum and Plasmodium lophurae . This mosquito also mechanically transmits some veterinary diseases . In 1952 Fenner et al. , found it transmitting the myxoma virus between rabbits and in 2001 Chihota et al. , the lumpy skin disease virus between cattle . The yellow fever mosquito can contribute to the spread of reticular cell sarcoma among Syrian hamsters . The Centers for Disease Control and Prevention traveler's page on preventing dengue fever suggests using mosquito repellents that contain DEET (N, N-diethylmetatoluamide, 20% to 30%). It also suggests: Insect repellents containing DEET (particularly concentrated products) or p -menthane-3,8-diol (from lemon eucalyptus ) were effective in repelling Ae. aegypti mosquitoes, while others were less effective or ineffective in a scientific study. The Centers for Disease Control and Prevention article on "Protection against Mosquitoes, Ticks, & Other Arthropods" notes that "Studies suggest that concentrations of DEET above approximately 50% do not offer a marked increase in protection time against mosquitoes; DEET efficacy tends to plateau at a concentration of approximately 50%". Other insect repellents recommended by the CDC include Picaridin (KBR 3023/ icaridin ), IR3535 , and 2-undecanone . Pyrethroids are commonly used. This widespread use of pyrethroids and DDT has caused Knockdown resistance ( kdr ) mutations. Almost no research has been done on the fitness implications. studies by Kumar et al. , 2009 on deltamethrin in India, Plernsub et al. , 2013 on permethrin in Thailand, by Jaramillo-O et al. , 2014 on λ-cyhalothrin in Colombia, by Alvarez-Gonzalez et al. , 2017 on deltamethrin in Venezuela, are all substantially confounded . As of 2019, understanding of selective pressure under withdrawal of insecticide is hence limited. Ae. aegypti has been genetically modified to suppress its own species in an approach similar to the sterile insect technique , thereby reducing the risk of disease. The mosquitoes, known as OX513A , were developed by Oxitec , a spinout of Oxford University . Field trials in the Cayman Islands , in Juazeiro , Brazil, by Carvalho et al. , 2015, and in Panama by Neira et al. , 2014 have shown that the OX513A mosquitoes reduced the target mosquito populations by more than 90%. This mosquito suppression effect is achieved by a self-limiting gene that prevents the offspring from surviving. Male modified mosquitoes, which do not bite or spread disease, are released to mate with the pest females. Their offspring inherit the self-limiting gene and die before reaching adulthood—before they can reproduce or spread disease. The OX513A mosquitoes and their offspring also carry a fluorescent marker for simple monitoring. To produce more OX513A mosquitoes for control projects, the self-limiting gene is switched off (using the Tet-Off system ) in the mosquito production facility using an antidote (the antibiotic tetracycline ), allowing the mosquitoes to reproduce naturally. In the environment, the antidote is unavailable to rescue mosquito reproduction, so the pest population is suppressed. The mosquito control effect is nontoxic and species-specific, as the OX513A mosquitoes are Ae. aegypti and only breed with Ae. aegypti . The result of the self-limiting approach is that the released insects and their offspring die and do not persist in the environment. In Brazil, the modified mosquitoes were approved by the National Biosecurity Technical Commission for releases throughout the country. Insects were released into the wild populations of Brazil, Malaysia, and the Cayman Islands in 2012. In July 2015, the city of Piracicaba , São Paulo, started releasing the OX513A mosquitoes. In 2015, the UK House of Lords called on the government to support more work on genetically modified insects in the interest of global health. In 2016, the United States Food and Drug Administration granted preliminary approval for the use of modified mosquitoes to prevent the spread of the Zika virus. Another proposed method consists in using radiation to sterilize male larvae so that when they mate, they produce no progeny. Male mosquitoes do not bite or spread disease. Using CRISPR/Cas9 based genome editing to engineer the genome of Aedes aegypti genes like ECFP (enhanced cyan fluorescent protein), Nix (male-determining factor gene), Aaeg-wtrw (Ae. aegypti water witch locus), Kmo (kynurenine 3-monoxygenase), loqs (loquacious), r2d2 (r2d2 protein), ku70 (ku heterodimer protein gene) and lig4 (ligase4) were targeted to modify the genome of Aedes aegypti . The new mutant will become incapable of pathogen transmission or result in population control. In 2016 research into the use of a bacterium called Wolbachia as a method of biocontrol was published showing that invasion of Ae. aegypti by the endosymbiotic bacteria allows mosquitos to be resistant to certain arboviruses such as dengue fever and Zika virus strains currently circulating. In 2017 Alphabet, Inc. started the Debug Project to infect males of this species with Wolbachia bacteria, interrupting the reproductive cycle of these animals. Pyrethroids are commonly used. This widespread use of pyrethroids and DDT has caused Knockdown resistance ( kdr ) mutations. Almost no research has been done on the fitness implications. studies by Kumar et al. , 2009 on deltamethrin in India, Plernsub et al. , 2013 on permethrin in Thailand, by Jaramillo-O et al. , 2014 on λ-cyhalothrin in Colombia, by Alvarez-Gonzalez et al. , 2017 on deltamethrin in Venezuela, are all substantially confounded . As of 2019, understanding of selective pressure under withdrawal of insecticide is hence limited. Ae. aegypti has been genetically modified to suppress its own species in an approach similar to the sterile insect technique , thereby reducing the risk of disease. The mosquitoes, known as OX513A , were developed by Oxitec , a spinout of Oxford University . Field trials in the Cayman Islands , in Juazeiro , Brazil, by Carvalho et al. , 2015, and in Panama by Neira et al. , 2014 have shown that the OX513A mosquitoes reduced the target mosquito populations by more than 90%. This mosquito suppression effect is achieved by a self-limiting gene that prevents the offspring from surviving. Male modified mosquitoes, which do not bite or spread disease, are released to mate with the pest females. Their offspring inherit the self-limiting gene and die before reaching adulthood—before they can reproduce or spread disease. The OX513A mosquitoes and their offspring also carry a fluorescent marker for simple monitoring. To produce more OX513A mosquitoes for control projects, the self-limiting gene is switched off (using the Tet-Off system ) in the mosquito production facility using an antidote (the antibiotic tetracycline ), allowing the mosquitoes to reproduce naturally. In the environment, the antidote is unavailable to rescue mosquito reproduction, so the pest population is suppressed. The mosquito control effect is nontoxic and species-specific, as the OX513A mosquitoes are Ae. aegypti and only breed with Ae. aegypti . The result of the self-limiting approach is that the released insects and their offspring die and do not persist in the environment. In Brazil, the modified mosquitoes were approved by the National Biosecurity Technical Commission for releases throughout the country. Insects were released into the wild populations of Brazil, Malaysia, and the Cayman Islands in 2012. In July 2015, the city of Piracicaba , São Paulo, started releasing the OX513A mosquitoes. In 2015, the UK House of Lords called on the government to support more work on genetically modified insects in the interest of global health. In 2016, the United States Food and Drug Administration granted preliminary approval for the use of modified mosquitoes to prevent the spread of the Zika virus. Another proposed method consists in using radiation to sterilize male larvae so that when they mate, they produce no progeny. Male mosquitoes do not bite or spread disease. Using CRISPR/Cas9 based genome editing to engineer the genome of Aedes aegypti genes like ECFP (enhanced cyan fluorescent protein), Nix (male-determining factor gene), Aaeg-wtrw (Ae. aegypti water witch locus), Kmo (kynurenine 3-monoxygenase), loqs (loquacious), r2d2 (r2d2 protein), ku70 (ku heterodimer protein gene) and lig4 (ligase4) were targeted to modify the genome of Aedes aegypti . The new mutant will become incapable of pathogen transmission or result in population control. In 2016 research into the use of a bacterium called Wolbachia as a method of biocontrol was published showing that invasion of Ae. aegypti by the endosymbiotic bacteria allows mosquitos to be resistant to certain arboviruses such as dengue fever and Zika virus strains currently circulating. In 2017 Alphabet, Inc. started the Debug Project to infect males of this species with Wolbachia bacteria, interrupting the reproductive cycle of these animals. Fungal species Erynia conica (from the family Entomophthoraceae ) infects (and kills) two types of mosquitos: Aedes aegypti and Culex restuans . Studies on the fungus have been carried out on its potiential use as a biological control of the mosquitos. The species was first named (as Culex aegypti ) in 1757 by Fredric Hasselquist in his treatise Iter Palaestinum . Hasselquist was provided with the names and descriptions by his mentor, Carl Linnaeus . This work was later translated into German and published in 1762 as Reise nach Palästina . Since the latter is an uncritical reproduction of the former, they are both considered to antedate the starting point for zoological nomenclature in 1758. Nonetheless, the name Aedes aegypti was frequently used, starting with H. G. Dyar in 1920. [ citation needed ] To stabilise the nomenclature, a petition to the International Commission on Zoological Nomenclature was made by P. F. Mattingly, Alan Stone, and Kenneth L. Knight in 1962. It also transpired that, although the name Aedes aegypti was universally used for the yellow fever mosquito, Linnaeus had actually described a species now known as Aedes ( Ochlerotatus ) caspius . In 1964, the commission ruled in favour of the proposal, validating Linnaeus' name, and transferring it to the species for which it was in general use. The yellow fever mosquito belongs to the tribe Aedini of the dipteran family Culicidae and to the genus Aedes and subgenus Stegomyia . According to one recent analysis, the subgenus Stegomyia of the genus Aedes should be raised to the level of genus. The proposed name change has been ignored by most scientists; at least one scientific journal, the Journal of Medical Entomology , has officially encouraged authors dealing with aedile mosquitoes to continue to use the traditional names, unless they have particular reasons for not doing so. The generic name comes from the Ancient Greek ἀηδής , aēdēs , meaning "unpleasant" or "odious". Two subspecies are commonly recognized: This classification is complicated by the results of Gloria-Soria et al. , 2016. Although confirming the existence of these two major subspecies, Gloria-Sora et al. finds greater worldwide diversity than previously recognized and a large number of distinct populations separated by various geographic factors. Two subspecies are commonly recognized: This classification is complicated by the results of Gloria-Soria et al. , 2016. Although confirming the existence of these two major subspecies, Gloria-Sora et al. finds greater worldwide diversity than previously recognized and a large number of distinct populations separated by various geographic factors.

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Chikungunya

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Ebola

Ebola , also known as Ebola virus disease ( EVD ) and Ebola hemorrhagic fever ( EHF ), is a viral hemorrhagic fever in humans and other primates , caused by ebolaviruses . Symptoms typically start anywhere between two days and three weeks after infection. The first symptoms are usually fever , sore throat , muscle pain , and headaches . These are usually followed by vomiting , diarrhoea , rash and decreased liver and kidney function, at which point some people begin to bleed both internally and externally. It kills between 25% and 90% of those infected – about 50% on average. Death is often due to shock from fluid loss , and typically occurs between six and 16 days after the first symptoms appear. Early treatment of symptoms increases the survival rate considerably compared to late start. An Ebola vaccine was approved by the US FDA in December 2019. The virus spreads through direct contact with body fluids , such as blood from infected humans or other animals, or from contact with items that have recently been contaminated with infected body fluids. There have been no documented cases, either in nature or under laboratory conditions, of spread through the air between humans or other primates . After recovering from Ebola, semen or breast milk may continue to carry the virus for anywhere between several weeks to several months. Fruit bats are believed to be the normal carrier in nature ; they are able to spread the virus without being affected by it. The symptoms of Ebola may resemble those of several other diseases, including malaria , cholera , typhoid fever , meningitis and other viral hemorrhagic fevers. Diagnosis is confirmed by testing blood samples for the presence of viral RNA , viral antibodies or the virus itself. Control of outbreaks requires coordinated medical services and community engagement, including rapid detection, contact tracing of those exposed, quick access to laboratory services, care for those infected, and proper disposal of the dead through cremation or burial. Prevention measures involve wearing proper protective clothing and washing hands when in close proximity to patients and while handling potentially infected bushmeat , as well as thoroughly cooking bushmeat. An Ebola vaccine was approved by the US FDA in December 2019. While there is no approved treatment for Ebola as of 2019 [ update ] , two treatments ( atoltivimab/maftivimab/odesivimab and ansuvimab ) are associated with improved outcomes. Supportive efforts also improve outcomes. These include oral rehydration therapy (drinking slightly sweetened and salty water) or giving intravenous fluids , and treating symptoms. In October 2020, atoltivimab/maftivimab/odesivimab (Inmazeb) was approved for medical use in the United States to treat the disease caused by Zaire ebolavirus . Ebola was first identified in 1976, in two simultaneous outbreaks, one in Nzara (a town in South Sudan ) and the other in Yambuku ( the Democratic Republic of the Congo ), a village near the Ebola River , for which the disease was named. Ebola outbreaks occur intermittently in tropical regions of sub-Saharan Africa . Between 1976 and 2012, according to the World Health Organization , there were 24 outbreaks of Ebola resulting in a total of 2,387 cases, and 1,590 deaths . The largest Ebola outbreak to date was an epidemic in West Africa from December 2013 to January 2016, with 28,646 cases and 11,323 deaths. On 29 March 2016, it was declared to no longer be an emergency. Other outbreaks in Africa began in the Democratic Republic of the Congo in May 2017, and 2018. In July 2019, the World Health Organization declared the Congo Ebola outbreak a world health emergency . The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, and usually between 4 and 10 days. However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. Symptoms usually begin with a sudden influenza -like stage characterised by fatigue , fever , weakness , decreased appetite , muscular pain , joint pain , headache, and sore throat. The fever is usually higher than 38.3 °C (101 °F) . This is often followed by nausea, vomiting, diarrhoea , abdominal pain, and sometimes hiccups . The combination of severe vomiting and diarrhoea often leads to severe dehydration . Next, shortness of breath and chest pain may occur, along with swelling , headaches , and confusion . In about half of the cases, the skin may develop a maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. In some cases, internal and external bleeding may occur. This typically begins five to seven days after the first symptoms. All infected people show some decreased blood clotting . Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. This may cause vomiting blood , coughing up of blood , or blood in stool . Bleeding into the skin may create petechiae , purpura , ecchymoses or haematomas (especially around needle injection sites). Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually in the gastrointestinal tract . The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, but in the 2014–15 outbreak in the US it was ~18%, possibly due to improved prevention of disseminated intravascular coagulation . Recovery may begin between seven and 14 days after first symptoms. Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to shock from fluid loss . In general, bleeding often indicates a worse outcome, and blood loss may result in death. People are often in a coma near the end of life. Those who survive often have ongoing muscular and joint pain, liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. Problems with vision may develop. It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. Survivors develop antibodies against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, and usually between 4 and 10 days. However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. Symptoms usually begin with a sudden influenza -like stage characterised by fatigue , fever , weakness , decreased appetite , muscular pain , joint pain , headache, and sore throat. The fever is usually higher than 38.3 °C (101 °F) . This is often followed by nausea, vomiting, diarrhoea , abdominal pain, and sometimes hiccups . The combination of severe vomiting and diarrhoea often leads to severe dehydration . Next, shortness of breath and chest pain may occur, along with swelling , headaches , and confusion . In about half of the cases, the skin may develop a maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. In some cases, internal and external bleeding may occur. This typically begins five to seven days after the first symptoms. All infected people show some decreased blood clotting . Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. This may cause vomiting blood , coughing up of blood , or blood in stool . Bleeding into the skin may create petechiae , purpura , ecchymoses or haematomas (especially around needle injection sites). Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually in the gastrointestinal tract . The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, but in the 2014–15 outbreak in the US it was ~18%, possibly due to improved prevention of disseminated intravascular coagulation . Recovery may begin between seven and 14 days after first symptoms. Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to shock from fluid loss . In general, bleeding often indicates a worse outcome, and blood loss may result in death. People are often in a coma near the end of life. Those who survive often have ongoing muscular and joint pain, liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. Problems with vision may develop. It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. Survivors develop antibodies against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. EVD in humans is caused by four of six viruses of the genus Ebolavirus . The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV) and one simply called Ebola virus (EBOV, formerly Zaire Ebola virus). EBOV, species Zaire ebolavirus , is the most dangerous of the known EVD-causing viruses, and is responsible for the largest number of outbreaks. The fifth and sixth viruses, Reston virus (RESTV) and Bombali virus (BOMV), are not thought to cause disease in humans, but have caused disease in other primates. All five viruses are closely related to marburgviruses . Ebolaviruses contain single-stranded, non-infectious RNA genomes . Ebolavirus genomes contain seven genes including 3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins , DC-SIGN , or integrins , which is followed by fusion of the viral envelope with cellular membranes . The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved. This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid . The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. The viral RNA polymerase , encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs , which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane . Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease. Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen . The WHO states that only people who are very sick are able to spread Ebola disease in saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit. Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. Ebola may be spread through large droplets ; however, this is believed to occur only when a person is very sick. This contamination can happen if a person is splashed with droplets. Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via sexual intercourse . Virus persistence in semen for over a year has been recorded in a national screening programme. Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood. Otherwise, people who have recovered are not infectious. The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low. Usually when someone has symptoms of the disease, they are unable to travel without assistance. Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk. Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. Health-care workers treating people with Ebola are at greatest risk of infection. The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. There has been transmission in hospitals in some African countries that reuse hypodermic needles. Some health-care centres caring for people with the disease do not have running water. In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates , but not from primates to primates. Spread of EBOV by water, or food other than bushmeat, has not been observed. No spread by mosquitos or other insects has been reported. Other possible methods of transmission are being studied. Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as baboons , great apes ( chimpanzees and gorillas ), and duikers (a species of antelope ). Animals may become infected when they eat fruit partially eaten by bats carrying the virus. Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate. Three types of fruit bats ( Hypsignathus monstrosus , Epomops franqueti and Myonycteris torquata ) were found to possibly carry the virus without getting sick. As of 2013 [ update ] , whether other animals are involved in its spread is not known. Plants, arthropods , rodents , and birds have also been considered possible viral reservoirs. Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys ) and one shrew ( Sylvisorex ollula ) collected from the Central African Republic . However, further research efforts have not confirmed rodents as a reservoir. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. Ebolaviruses contain single-stranded, non-infectious RNA genomes . Ebolavirus genomes contain seven genes including 3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins , DC-SIGN , or integrins , which is followed by fusion of the viral envelope with cellular membranes . The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved. This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid . The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. The viral RNA polymerase , encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs , which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane . Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease. Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen . The WHO states that only people who are very sick are able to spread Ebola disease in saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit. Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. Ebola may be spread through large droplets ; however, this is believed to occur only when a person is very sick. This contamination can happen if a person is splashed with droplets. Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via sexual intercourse . Virus persistence in semen for over a year has been recorded in a national screening programme. Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood. Otherwise, people who have recovered are not infectious. The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low. Usually when someone has symptoms of the disease, they are unable to travel without assistance. Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk. Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. Health-care workers treating people with Ebola are at greatest risk of infection. The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. There has been transmission in hospitals in some African countries that reuse hypodermic needles. Some health-care centres caring for people with the disease do not have running water. In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates , but not from primates to primates. Spread of EBOV by water, or food other than bushmeat, has not been observed. No spread by mosquitos or other insects has been reported. Other possible methods of transmission are being studied. Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as baboons , great apes ( chimpanzees and gorillas ), and duikers (a species of antelope ). Animals may become infected when they eat fruit partially eaten by bats carrying the virus. Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate. Three types of fruit bats ( Hypsignathus monstrosus , Epomops franqueti and Myonycteris torquata ) were found to possibly carry the virus without getting sick. As of 2013 [ update ] , whether other animals are involved in its spread is not known. Plants, arthropods , rodents , and birds have also been considered possible viral reservoirs. Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys ) and one shrew ( Sylvisorex ollula ) collected from the Central African Republic . However, further research efforts have not confirmed rodents as a reservoir. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. Like other filoviruses , EBOV replicates very efficiently in many cells , producing large amounts of virus in monocytes , macrophages , dendritic cells and other cells including liver cells , fibroblasts , and adrenal gland cells . Viral replication triggers high levels of inflammatory chemical signals and leads to a septic state . EBOV is thought to infect humans through contact with mucous membranes or skin breaks. After infection, endothelial cells (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as macrophages, monocytes , and dendritic cells are the main targets of attack. Following infection, immune cells carry the virus to nearby lymph nodes where further reproduction of the virus takes place. From there the virus can enter the bloodstream and lymphatic system and spread throughout the body. Macrophages are the first cells infected with the virus, and this infection results in programmed cell death . Other types of white blood cells , such as lymphocytes , also undergo programmed cell death leading to an abnormally low concentration of lymphocytes in the blood. This contributes to the weakened immune response seen in those infected with EBOV. Endothelial cells may be infected within three days after exposure to the virus. The breakdown of endothelial cells leading to blood vessel injury can be attributed to EBOV glycoproteins . This damage occurs due to the synthesis of Ebola virus glycoprotein (GP), which reduces the availability of specific integrins responsible for cell adhesion to the intercellular structure and causes liver damage, leading to improper clotting . The widespread bleeding that occurs in affected people causes swelling and shock due to loss of blood volume . The dysfunctional bleeding and clotting commonly seen in EVD has been attributed to increased activation of the extrinsic pathway of the coagulation cascade due to excessive tissue factor production by macrophages and monocytes. After infection, a secreted glycoprotein , small soluble glycoprotein (sGP or GP) is synthesised. EBOV replication overwhelms protein synthesis of infected cells and the host immune defences. The GP forms a trimeric complex , which tethers the virus to the endothelial cells. The sGP forms a dimeric protein that interferes with the signalling of neutrophils , another type of white blood cell. This enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. [ medical citation needed ] Furthermore, the virus is capable of hijacking cellular metabolism. Studies have shown that Ebola virus-like particles can reprogram metabolism in both vascular and immune cells. Filoviral infection also interferes with proper functioning of the innate immune system . EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha , interferon-beta , and interferon gamma . The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5 ) or outside of the cytosol (such as Toll-like receptor 3 (TLR3) , TLR7 , TLR8 and TLR9 ) recognise infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signalling cascade that leads to the expression of type 1 interferons . The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighbouring cell. Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins STAT1 and STAT2 are activated and move to the cell's nucleus . This triggers the expression of interferon-stimulated genes , which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body. Filoviral infection also interferes with proper functioning of the innate immune system . EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha , interferon-beta , and interferon gamma . The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5 ) or outside of the cytosol (such as Toll-like receptor 3 (TLR3) , TLR7 , TLR8 and TLR9 ) recognise infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signalling cascade that leads to the expression of type 1 interferons . The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighbouring cell. Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins STAT1 and STAT2 are activated and move to the cell's nucleus . This triggers the expression of interferon-stimulated genes , which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body. When EVD is suspected, travel, work history, and exposure to wildlife are important factors with respect to further diagnostic efforts. Possible non-specific laboratory indicators of EVD include a low platelet count ; an initially decreased white blood cell count followed by an increased white blood cell count ; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time , partial thromboplastin time , and bleeding time . Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy . The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture , detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected six to 18 days after symptom onset. During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA. In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever . The symptoms are also similar to those of other viral haemorrhagic fevers such as Marburg virus disease , Crimean–Congo haemorrhagic fever , and Lassa fever . The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever , shigellosis , rickettsial diseases , cholera , sepsis , borreliosis , EHEC enteritis , leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , measles , and viral hepatitis among others. Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukaemia , haemolytic uraemic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary haemorrhagic telangiectasia , Kawasaki disease , and warfarin poisoning. Possible non-specific laboratory indicators of EVD include a low platelet count ; an initially decreased white blood cell count followed by an increased white blood cell count ; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time , partial thromboplastin time , and bleeding time . Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy . The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture , detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected six to 18 days after symptom onset. During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA. In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever . The symptoms are also similar to those of other viral haemorrhagic fevers such as Marburg virus disease , Crimean–Congo haemorrhagic fever , and Lassa fever . The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever , shigellosis , rickettsial diseases , cholera , sepsis , borreliosis , EHEC enteritis , leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , measles , and viral hepatitis among others. Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukaemia , haemolytic uraemic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary haemorrhagic telangiectasia , Kawasaki disease , and warfarin poisoning. An Ebola vaccine , rVSV-ZEBOV , was approved in the United States in December 2019. It appears to be fully effective ten days after being given. It was studied in Guinea between 2014 and 2016. More than 100,000 people have been vaccinated against Ebola as of 2019 [ update ] . The WHO reported that approximately 345,000 people were given the vaccine during the Kivu Ebola epidemic from 2018 to 2020. Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. Quarantine, also known as enforced isolation, is usually effective in decreasing spread. Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. In the United States, the law allows quarantine of those infected with ebolaviruses. Contact tracing is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. An Ebola vaccine , rVSV-ZEBOV , was approved in the United States in December 2019. It appears to be fully effective ten days after being given. It was studied in Guinea between 2014 and 2016. More than 100,000 people have been vaccinated against Ebola as of 2019 [ update ] . The WHO reported that approximately 345,000 people were given the vaccine during the Kivu Ebola epidemic from 2018 to 2020. Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. Quarantine, also known as enforced isolation, is usually effective in decreasing spread. Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. In the United States, the law allows quarantine of those infected with ebolaviruses. Contact tracing is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. As of 2019 [ update ] two treatments ( atoltivimab/maftivimab/odesivimab and ansuvimab ) are associated with improved outcomes. The U.S. Food and Drug Administration (FDA) advises people to be careful of advertisements making unverified or fraudulent claims of benefits supposedly gained from various anti-Ebola products. In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab with an indication for the treatment of infection caused by Zaire ebolavirus . Treatment is primarily supportive in nature. Early supportive care with rehydration and symptomatic treatment improves survival. Rehydration may be via the oral or intravenous route. These measures may include pain management , and treatment for nausea , fever , and anxiety . The World Health Organization (WHO) recommends avoiding aspirin or ibuprofen for pain management, due to the risk of bleeding associated with these medications. Blood products such as packed red blood cells , platelets , or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, though there is no evidence to suggest such treatment helps. Several experimental treatments are being studied . Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. Intensive care is often used in the developed world. This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. Dialysis may be needed for kidney failure , and extracorporeal membrane oxygenation may be used for lung dysfunction. Treatment is primarily supportive in nature. Early supportive care with rehydration and symptomatic treatment improves survival. Rehydration may be via the oral or intravenous route. These measures may include pain management , and treatment for nausea , fever , and anxiety . The World Health Organization (WHO) recommends avoiding aspirin or ibuprofen for pain management, due to the risk of bleeding associated with these medications. Blood products such as packed red blood cells , platelets , or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, though there is no evidence to suggest such treatment helps. Several experimental treatments are being studied . Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. Intensive care is often used in the developed world. This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. Dialysis may be needed for kidney failure , and extracorporeal membrane oxygenation may be used for lung dysfunction. EVD has a risk of death in those infected of between 25% and 90%. As of September 2014 [ update ] , the average risk of death among those infected is 50%. The highest risk of death was 90% in the 2002–2003 Republic of the Congo outbreak. Early admission significantly increases survival rates Death, if it occurs, follows typically six to sixteen days after symptoms appear and is often due to low blood pressure from fluid loss . Early supportive care to prevent dehydration may reduce the risk of death. If an infected person survives, recovery may be quick and complete. However, a large portion of survivors develop post-Ebola virus syndrome after the acute phase of the infection. Prolonged cases are often complicated by the occurrence of long-term problems, such as inflammation of the testicles , joint pains , fatigue, hearing loss, mood and sleep disturbances, muscular pain , abdominal pain, menstrual abnormalities , miscarriages , skin peeling , or hair loss . Inflammation and swelling of the uveal layer of the eye is the most common eye complication in survivors of Ebola virus disease. Eye symptoms, such as light sensitivity , excess tearing , and vision loss have been described. Ebola can stay in some body parts like the eyes, breasts, and testicles after infection. Sexual transmission after recovery has been suspected. If sexual transmission occurs following recovery it is believed to be a rare event. One case of a condition similar to meningitis has been reported many months after recovery, as of October 2015 [ update ] . If an infected person survives, recovery may be quick and complete. However, a large portion of survivors develop post-Ebola virus syndrome after the acute phase of the infection. Prolonged cases are often complicated by the occurrence of long-term problems, such as inflammation of the testicles , joint pains , fatigue, hearing loss, mood and sleep disturbances, muscular pain , abdominal pain, menstrual abnormalities , miscarriages , skin peeling , or hair loss . Inflammation and swelling of the uveal layer of the eye is the most common eye complication in survivors of Ebola virus disease. Eye symptoms, such as light sensitivity , excess tearing , and vision loss have been described. Ebola can stay in some body parts like the eyes, breasts, and testicles after infection. Sexual transmission after recovery has been suspected. If sexual transmission occurs following recovery it is believed to be a rare event. One case of a condition similar to meningitis has been reported many months after recovery, as of October 2015 [ update ] . The disease typically occurs in outbreaks in tropical regions of Sub-Saharan Africa . From 1976 (when it was first identified) through 2013, the WHO reported 2,387 confirmed cases with 1,590 overall fatalities. The largest outbreak to date was the Ebola virus epidemic in West Africa , which caused a large number of deaths in Guinea , Sierra Leone , and Liberia . The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. In 2000, Uganda had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a genus Ebolavirus outbreak to date. In 2004, a Russian scientist died from Ebola after sticking herself with an infected needle. Between April and August 2007, a fever epidemic in a four-village region of the DRC was confirmed in September to have been cases of Ebola. Many people who attended the recent funeral of a local village chief died. The 2007 outbreak eventually infected 264 individuals and killed 187. On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of genus Ebolavirus , which was tentatively named Bundibugyo. The WHO reported 149 cases of this new strain and 37 of those led to deaths. The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant in the eastern region. Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana. In 2014, an outbreak occurred in the DRC. Genome-sequencing showed that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak , but was the same EBOV species, the Zaire species. It began in August 2014, and was declared over in November with 66 cases and 49 deaths. This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire . In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea , a West African nation. Researchers traced the outbreak to a one-year-old child who died in December 2013. The disease rapidly spread to the neighbouring countries of Liberia and Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital, Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long." Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases. It caused significant mortality, with a considerable case fatality rate . [note 1] By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. As of 8 May 2016 [ update ] , 28,646 suspected cases and 11,323 deaths were reported; however, the WHO said that these numbers may be underestimated. Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. A new case was detected in Sierra Leone on 14 January 2016. However, the outbreak was declared no longer an emergency on 29 March 2016. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the Bikoro , Iboko, and Wangata areas in Equateur province, including in the large city of Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. On 13 May 2018, WHO Director-General Tedros Adhanom Ghebreyesus visited Bikoro. Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as epidemiologists and officials trying to assess the outbreak and containment efforts. The 2018 outbreak in the DRC was declared over on 24 July 2018. On 1 August 2018, the world's 10th Ebola outbreak was declared in North Kivu province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. As of 4 June 2019 [ update ] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. In June 2019, two people died of Ebola in neighbouring Uganda . In July 2019, an infected man travelled to Goma , home to more than two million people. One week later, on 17 July 2019, the WHO declared the Ebola outbreak a global health emergency , the fifth time such a declaration has been made by the organisation. A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. On 25 June 2020, the second biggest EVD outbreak ever was declared over. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. The 11th EVD outbreak was officially declared over on 19 November 2020. By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths. On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 23 April 2022, a case of Ebola was confirmed in the DRC in the Equateur province. The case was a 31-year-old man whose symptoms began on 5 April, but did not seek treatment for over a week. On 21 April, he was admitted to an Ebola treatment centre and died later that day. By 24 May 2022, there were 5 recorded deaths in the DRC. On 15 August, the fifth case was buried, and the outbreak was declared over, 42 days after, on 4 July 2022. In September 2022, Uganda reported 7 cases infected with the Ebola Sudan strain , but by mid-October the count had increased to 63. In November 2022, the outbreak in Uganda continued - still without a vaccine. On 10 January 2023, the outbreak was considered over after no new cases had been reported for 42 days; the outbreak killed nearly 80 people. The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. In 2000, Uganda had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a genus Ebolavirus outbreak to date. In 2004, a Russian scientist died from Ebola after sticking herself with an infected needle. Between April and August 2007, a fever epidemic in a four-village region of the DRC was confirmed in September to have been cases of Ebola. Many people who attended the recent funeral of a local village chief died. The 2007 outbreak eventually infected 264 individuals and killed 187. On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of genus Ebolavirus , which was tentatively named Bundibugyo. The WHO reported 149 cases of this new strain and 37 of those led to deaths. The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant in the eastern region. Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana. In 2014, an outbreak occurred in the DRC. Genome-sequencing showed that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak , but was the same EBOV species, the Zaire species. It began in August 2014, and was declared over in November with 66 cases and 49 deaths. This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire . In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea , a West African nation. Researchers traced the outbreak to a one-year-old child who died in December 2013. The disease rapidly spread to the neighbouring countries of Liberia and Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital, Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long." Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases. It caused significant mortality, with a considerable case fatality rate . [note 1] By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. As of 8 May 2016 [ update ] , 28,646 suspected cases and 11,323 deaths were reported; however, the WHO said that these numbers may be underestimated. Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. A new case was detected in Sierra Leone on 14 January 2016. However, the outbreak was declared no longer an emergency on 29 March 2016. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the Bikoro , Iboko, and Wangata areas in Equateur province, including in the large city of Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. On 13 May 2018, WHO Director-General Tedros Adhanom Ghebreyesus visited Bikoro. Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as epidemiologists and officials trying to assess the outbreak and containment efforts. The 2018 outbreak in the DRC was declared over on 24 July 2018. On 1 August 2018, the world's 10th Ebola outbreak was declared in North Kivu province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. As of 4 June 2019 [ update ] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. In June 2019, two people died of Ebola in neighbouring Uganda . In July 2019, an infected man travelled to Goma , home to more than two million people. One week later, on 17 July 2019, the WHO declared the Ebola outbreak a global health emergency , the fifth time such a declaration has been made by the organisation. A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. On 25 June 2020, the second biggest EVD outbreak ever was declared over. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. The 11th EVD outbreak was officially declared over on 19 November 2020. By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths.On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 23 April 2022, a case of Ebola was confirmed in the DRC in the Equateur province. The case was a 31-year-old man whose symptoms began on 5 April, but did not seek treatment for over a week. On 21 April, he was admitted to an Ebola treatment centre and died later that day. By 24 May 2022, there were 5 recorded deaths in the DRC. On 15 August, the fifth case was buried, and the outbreak was declared over, 42 days after, on 4 July 2022. In September 2022, Uganda reported 7 cases infected with the Ebola Sudan strain , but by mid-October the count had increased to 63. In November 2022, the outbreak in Uganda continued - still without a vaccine. On 10 January 2023, the outbreak was considered over after no new cases had been reported for 42 days; the outbreak killed nearly 80 people. Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponised for use in biological warfare , and was investigated by Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air. Fake emails pretending to be Ebola information from the WHO or the Mexican government have, in 2014, been misused to spread computer malware. The BBC reported in 2015 that "North Korean state media has suggested the disease was created by the U.S. military as a biological weapon." Richard Preston 's 1995 best-selling book, The Hot Zone , dramatised the Ebola outbreak in Reston, Virginia. William Close 's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire. Tom Clancy 's 1996 novel, Executive Orders , involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka ). As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease. Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponised for use in biological warfare , and was investigated by Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air. Fake emails pretending to be Ebola information from the WHO or the Mexican government have, in 2014, been misused to spread computer malware. The BBC reported in 2015 that "North Korean state media has suggested the disease was created by the U.S. military as a biological weapon." Richard Preston 's 1995 best-selling book, The Hot Zone , dramatised the Ebola outbreak in Reston, Virginia. William Close 's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire. Tom Clancy 's 1996 novel, Executive Orders , involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka ). As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease. Ebola has a high mortality rate among primates. Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas. Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in the 420 km 2 Lossi Sanctuary between 2002 and 2003. Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not. Recovered gorilla carcasses have contained multiple Ebola virus strains, suggesting multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting that transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoirs and animal populations. In 2012, it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus nine percent of those farther away. The authors concluded that there were "potential implications for preventing and controlling human outbreaks." In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia , had an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian haemorrhagic fever virus (SHFV) and occurred amongst a shipment of crab-eating macaque monkeys imported from the Philippines. Hazelton's veterinary pathologist in Reston sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland , where an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV. An electron microscopist from USAMRIID discovered filoviruses similar in appearance, in crystalloid aggregates and as single filaments with a shepherd's hook, to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit. A US Army team headquartered at USAMRIID euthanised the surviving monkeys, and brought all the dead monkeys to Fort Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions. Blood samples were taken from 178 animal handlers during the incident. Of those, six animal handlers eventually seroconverted , including one who had cut himself with a bloody scalpel. Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans. The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident. Reston virus (RESTV) can be transmitted to pigs. Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy, where the virus had infected pigs. According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus . Pigs that have been infected with RESTV tend to show symptoms of the disease. Ebola has a high mortality rate among primates. Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas. Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in the 420 km 2 Lossi Sanctuary between 2002 and 2003. Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not. Recovered gorilla carcasses have contained multiple Ebola virus strains, suggesting multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting that transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoirs and animal populations. In 2012, it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus nine percent of those farther away. The authors concluded that there were "potential implications for preventing and controlling human outbreaks."In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia , had an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian haemorrhagic fever virus (SHFV) and occurred amongst a shipment of crab-eating macaque monkeys imported from the Philippines. Hazelton's veterinary pathologist in Reston sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland , where an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV. An electron microscopist from USAMRIID discovered filoviruses similar in appearance, in crystalloid aggregates and as single filaments with a shepherd's hook, to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit. A US Army team headquartered at USAMRIID euthanised the surviving monkeys, and brought all the dead monkeys to Fort Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions. Blood samples were taken from 178 animal handlers during the incident. Of those, six animal handlers eventually seroconverted , including one who had cut himself with a bloody scalpel. Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans. The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident. Reston virus (RESTV) can be transmitted to pigs. Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy, where the virus had infected pigs. According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus . Pigs that have been infected with RESTV tend to show symptoms of the disease. As of July 2015 [ update ] , no medication has been proven safe and effective for treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014, and early 2015, but some were abandoned due to lack of efficacy or lack of people to study. As of August 2019 [ update ] , two experimental treatments known as atoltivimab/maftivimab/odesivimab and ansuvimab were found to be 90% effective. The diagnostic tests currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. On 29 November 2014, a new 15-minute Ebola test was reported that if successful, "not only gives patients a better chance of survival, but it prevents transmission of the virus to other people." The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. On 29 December 2014, the U.S. Food and Drug Administration (FDA) approved the LightMix Ebola Zaire rRT-PCR test for patients with symptoms of Ebola. Animal models and in particular non-human primates are being used to study different aspects of Ebola virus disease. Developments in organ-on-a-chip technology have led to a chip-based model for Ebola haemorrhagic syndrome. As of July 2015 [ update ] , no medication has been proven safe and effective for treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014, and early 2015, but some were abandoned due to lack of efficacy or lack of people to study. As of August 2019 [ update ] , two experimental treatments known as atoltivimab/maftivimab/odesivimab and ansuvimab were found to be 90% effective. The diagnostic tests currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. On 29 November 2014, a new 15-minute Ebola test was reported that if successful, "not only gives patients a better chance of survival, but it prevents transmission of the virus to other people." The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. On 29 December 2014, the U.S. Food and Drug Administration (FDA) approved the LightMix Ebola Zaire rRT-PCR test for patients with symptoms of Ebola. Animal models and in particular non-human primates are being used to study different aspects of Ebola virus disease. Developments in organ-on-a-chip technology have led to a chip-based model for Ebola haemorrhagic syndrome.

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Chikungunya

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Rabies

Rabies is a viral disease that causes encephalitis in humans and other mammals . It was historically referred to as hydrophobia ("fear of water") due to the symptom of panic when presented with liquids to drink. Early symptoms can include fever and abnormal sensations at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, violent movements, uncontrolled excitement, fear of water, an inability to move parts of the body, confusion, and loss of consciousness . Once symptoms appear, the result is virtually always death. The time period between contracting the disease and the start of symptoms is usually one to three months but can vary from less than one week to more than one year. The time depends on the distance the virus must travel along peripheral nerves to reach the central nervous system . Rabies is caused by lyssaviruses , including the rabies virus and Australian bat lyssavirus . It is spread when an infected animal bites or scratches a human or other animals. Saliva from an infected animal can also transmit rabies if the saliva comes into contact with the eyes, mouth, or nose. Globally, dogs are the most common animal involved. In countries where dogs commonly have the disease, more than 99% of rabies cases are the direct result of dog bites . In the Americas , bat bites are the most common source of rabies infections in humans, and less than 5% of cases are from dogs. Rodents are very rarely infected with rabies. The disease can be diagnosed only after the start of symptoms. Animal control and vaccination programs have decreased the risk of rabies from dogs in a number of regions of the world. Immunizing people before they are exposed is recommended for those at high risk, including those who work with bats or who spend prolonged periods in areas of the world where rabies is common. In people who have been exposed to rabies, the rabies vaccine and sometimes rabies immunoglobulin are effective in preventing the disease if the person receives the treatment before the start of rabies symptoms. Washing bites and scratches for 15 minutes with soap and water, povidone-iodine , or detergent may reduce the number of viral particles and may be somewhat effective at preventing transmission. As of 2016 [ update ] , only fourteen people were documented to have survived a rabies infection after showing symptoms. However, research conducted in 2010 among a population of people in Peru with a self-reported history of one or more bites from vampire bats (commonly infected with rabies), found that out of 73 individuals reporting previous bat bites, seven people had rabies virus-neutralizing antibodies (rVNA). Since only one member of this group reported prior vaccination for rabies, the findings of the research suggest previously undocumented cases of infection and viral replication followed by an abortive infection. This could indicate that people may have an exposure to the virus without treatment and develop natural antibodies as a result. Rabies causes about 59,000 deaths worldwide per year, about 40% of which are in children under the age of 15. More than 95% of human deaths from rabies occur in Africa and Asia. Rabies is present in more than 150 countries and on all continents but Antarctica. More than 3 billion people live in regions of the world where rabies occurs. A number of countries, including Australia and Japan, as well as much of Western Europe, do not have rabies among dogs. Many Pacific islands do not have rabies at all. It is classified as a neglected tropical disease . The name rabies is derived from the Latin rabies , "madness". The Greeks derived the word lyssa , from lud or "violent"; this root is used in the genus name of the rabies virus, Lyssavirus . The period between infection and the first symptoms (incubation period) is typically one to three months in humans. This period may be as short as four days or longer than six years, depending on the location and severity of the wound and the amount of virus introduced. Initial symptoms of rabies are often nonspecific such as fever and headache. As rabies progresses and causes inflammation of the brain and meninges , symptoms can include slight or partial paralysis , anxiety , insomnia , confusion , agitation , abnormal behavior, paranoia , terror , and hallucinations . The person may also have fear of water. The symptoms eventually progress to delirium , and coma . Death usually occurs two to ten days after first symptoms. Survival is almost unknown once symptoms have presented, even with intensive care. Rabies has also occasionally been referred to as hydrophobia ("fear of water") throughout its history. It refers to a set of symptoms in the later stages of an infection in which the person has difficulty swallowing, shows panic when presented with liquids to drink, and cannot quench their thirst. Saliva production is greatly increased, and attempts to drink, or even the intention or suggestion of drinking, may cause excruciatingly painful spasms of the muscles in the throat and larynx . Since the infected individual cannot swallow saliva and water, the virus has a much higher chance of being transmitted, because it multiplies and accumulates in the salivary glands and is transmitted through biting. Hydrophobia is commonly associated with furious rabies, which affects 80% of rabies-infected people. This form of rabies causes irrational aggression in the host, which aids in the spreading of the virus through animal bites; [ medical citation needed ] a "foaming at the mouth" effect, caused by the accumulation of saliva, is also commonly associated with rabies in the public perception and in popular culture. The remaining 20% may experience a paralytic form of rabies that is marked by muscle weakness , loss of sensation, and paralysis ; this form of rabies does not usually cause fear of water. Rabies is caused by a number of lyssaviruses including the rabies virus and Australian bat lyssavirus . Duvenhage lyssavirus may cause a rabies-like infection. The rabies virus is the type species of the Lyssavirus genus , in the family Rhabdoviridae , order Mononegavirales . Lyssavirions have helical symmetry, with a length of about 180 nm and a cross-section of about 75 nm. These virions are enveloped and have a single-stranded RNA genome with negative sense . The genetic information is packed as a ribonucleoprotein complex in which RNA is tightly bound by the viral nucleoprotein. The RNA genome of the virus encodes five genes whose order is highly conserved: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and the viral RNA polymerase (L). To enter cells, trimeric spikes on the exterior of the membrane of the virus interact with a specific cell receptor, the most likely one being the acetylcholine receptor. The cellular membrane pinches in a procession known as pinocytosis and allows entry of the virus into the cell by way of an endosome . The virus then uses the acidic environment, which is necessary, of that endosome and binds to its membrane simultaneously, releasing its five proteins and single-strand RNA into the cytoplasm. Once within a muscle or nerve cell, the virus undergoes replication. The L protein then transcribes five mRNA strands and a positive strand of RNA all from the original negative strand RNA using free nucleotides in the cytoplasm. These five mRNA strands are then translated into their corresponding proteins (P, L, N, G and M proteins) at free ribosomes in the cytoplasm. Some proteins require post-translational modifications. For example, the G protein travels through the rough endoplasmic reticulum , where it undergoes further folding, and is then transported to the Golgi apparatus , where a sugar group is added to it ( glycosylation ). When there are enough viral proteins, the viral polymerase will begin to synthesize new negative strands of RNA from the template of the positive-strand RNA. These negative strands will then form complexes with the N, P, L and M proteins and then travel to the inner membrane of the cell, where a G protein has embedded itself in the membrane. The G protein then coils around the N-P-L-M complex of proteins taking some of the host cell membrane with it, which will form the new outer envelope of the virus particle. The virus then buds from the cell. From the point of entry, the virus is neurotropic , traveling along the neural pathways into the central nervous system . The virus usually first infects muscle cells close to the site of infection, where they are able to replicate without being 'noticed' by the host's immune system. Once enough virus has been replicated, they begin to bind to acetylcholine receptors at the neuromuscular junction. The virus then travels through the nerve cell axon via retrograde transport , as its P protein interacts with dynein , a protein present in the cytoplasm of nerve cells. Once the virus reaches the cell body it travels rapidly to the central nervous system (CNS), replicating in motor neurons and eventually reaching the brain. After the brain is infected, the virus travels centrifugally to the peripheral and autonomic nervous systems, eventually migrating to the salivary glands, where it is ready to be transmitted to the next host. : 317All warm-blooded species, including humans, may become infected with the rabies virus and develop symptoms. Birds were first artificially infected with rabies in 1884; however, infected birds are largely, if not wholly, asymptomatic, and recover. Other bird species have been known to develop rabies antibodies , a sign of infection, after feeding on rabies-infected mammals. The virus has also adapted to grow in cells of cold-blooded vertebrates. Most animals can be infected by the virus and can transmit the disease to humans. Worldwide, about 99% of human rabies cases come from domestic dogs. Other sources of rabies in humans include bats , monkeys , raccoons , foxes , skunks , cattle , wolves , coyotes , cats , and mongooses (normally either the small Asian mongoose or the yellow mongoose). Rabies may also spread through exposure to infected bears , domestic farm animals , groundhogs , weasels , and other wild carnivorans . However, lagomorphs , such as hares and rabbits , and small rodents , such as chipmunks , gerbils , guinea pigs , hamsters , mice , rats , and squirrels , are almost never found to be infected with rabies and are not known to transmit rabies to humans. Bites from mice, rats, or squirrels rarely require rabies prevention because these rodents are typically killed by any encounter with a larger, rabid animal, and would, therefore, not be carriers. The Virginia opossum (a marsupial, unlike the other mammals named in this paragraph, which are all eutherians / placental ), has a lower internal body temperature than the rabies virus prefers and therefore is resistant but not immune to rabies. Marsupials , along with monotremes ( platypuses and echidnas ), typically have lower body temperatures than similarly sized eutherians . The virus is usually present in the nerves and saliva of a symptomatic rabid animal. The route of infection is usually, but not always, by a bite. In many cases, the infected animal is exceptionally aggressive, may attack without provocation, and exhibits otherwise uncharacteristic behavior. This is an example of a viral pathogen modifying the behavior of its host to facilitate its transmission to other hosts. After a typical human infection by bite, the virus enters the peripheral nervous system . It then travels retrograde along the efferent nerves toward the central nervous system . During this phase, the virus cannot be easily detected within the host, and vaccination may still confer cell-mediated immunity to prevent symptomatic rabies. When the virus reaches the brain , it rapidly causes encephalitis , the prodromal phase, which is the beginning of the symptoms. Once the patient becomes symptomatic, treatment is almost never effective and mortality is over 99%. Rabies may also inflame the spinal cord , producing transverse myelitis . Although it is theoretically possible for rabies-infected humans to transmit it to others by biting or otherwise, no such cases have ever been documented, because infected humans are usually hospitalized and necessary precautions taken. Casual contact, such as touching a person with rabies or contact with non-infectious fluid or tissue (urine, blood, feces), does not constitute an exposure and does not require post-exposure prophylaxis. But as the virus is present in sperm and vaginal secretions, it might be possible for rabies to spread through sex. There are only a small number of recorded cases of human-to-human transmission of rabies, and all occurred through organ transplants , most frequently with corneal transplantation , from infected donors. Rabies can be difficult to diagnose because, in the early stages, it is easily confused with other diseases or even with a simple aggressive temperament. The reference method for diagnosing rabies is the fluorescent antibody test (FAT), an immunohistochemistry procedure, which is recommended by the World Health Organization (WHO). The FAT relies on the ability of a detector molecule (usually fluorescein isothiocyanate) coupled with a rabies-specific antibody, forming a conjugate, to bind to and allow the visualisation of rabies antigen using fluorescent microscopy techniques. Microscopic analysis of samples is the only direct method that allows for the identification of rabies virus-specific antigen in a short time and at a reduced cost, irrespective of geographical origin and status of the host. It has to be regarded as the first step in diagnostic procedures for all laboratories. Autolysed samples can, however, reduce the sensitivity and specificity of the FAT. The RT PCR assays proved to be a sensitive and specific tool for routine diagnostic purposes, particularly in decomposed samples or archival specimens. The diagnosis can be reliably made from brain samples taken after death. The diagnosis can also be made from saliva, urine, and cerebrospinal fluid samples, but this is not as sensitive or reliable as brain samples. Cerebral inclusion bodies called Negri bodies are 100% diagnostic for rabies infection but are found in only about 80% of cases. If possible, the animal from which the bite was received should also be examined for rabies. Some light microscopy techniques may also be used to diagnose rabies at a tenth of the cost of traditional fluorescence microscopy techniques, allowing identification of the disease in less-developed countries. A test for rabies, known as LN34, is easier to run on a dead animal's brain and might help determine who does and does not need post-exposure prevention. The test was developed by the Centers for Disease Control and Prevention (CDC) in 2018. The differential diagnosis in a case of suspected human rabies may initially include any cause of encephalitis , in particular infection with viruses such as herpesviruses , enteroviruses , and arboviruses such as West Nile virus . The most important viruses to rule out are herpes simplex virus type one, varicella zoster virus , and (less commonly) enteroviruses, including coxsackieviruses , echoviruses , polioviruses , and human enteroviruses 68 to 71. New causes of viral encephalitis are also possible, as was evidenced by the 1999 outbreak in Malaysia of 300 cases of encephalitis with a mortality rate of 40% caused by Nipah virus , a newly recognized paramyxovirus . Likewise, well-known viruses may be introduced into new locales, as is illustrated by the outbreak of encephalitis due to West Nile virus in the eastern United States. Almost all human exposure to rabies was fatal until a vaccine was developed in 1885 by Louis Pasteur and Émile Roux . Their original vaccine was harvested from infected rabbits, from which the virus in the nerve tissue was weakened by allowing it to dry for five to ten days. Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines. The human diploid cell rabies vaccine was started in 1967. Less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available. A recombinant vaccine called V-RG has been used in Belgium, France, Germany, and the United States to prevent outbreaks of rabies in undomesticated animals. Immunization before exposure has been used in both human and nonhuman populations, where, as in many jurisdictions, domesticated animals are required to be vaccinated. The Missouri Department of Health and Senior Services Communicable Disease Surveillance 2007 Annual Report states the following can help reduce the risk of contracting rabies: Vaccinating dogs, cats, and ferrets against rabies Keeping pets under supervision Not handling wild animals or strays Contacting an animal control officer upon observing a wild animal or a stray, especially if the animal is acting strangely If bitten by an animal, washing the wound with soap and water for 10 to 15 minutes and contacting a healthcare provider to determine if post-exposure prophylaxis is required 28 September is World Rabies Day , which promotes the information, prevention, and elimination of the disease. In Asia and in parts of the Americas and Africa, dogs remain the principal host. Mandatory vaccination of animals is less effective in rural areas. Especially in developing countries, pets may not be privately kept and their destruction may be unacceptable. Oral vaccines can be safely distributed in baits, a practice that has successfully reduced rabies in rural areas of Canada , France , and the United States . In Montreal , Quebec, Canada, baits are successfully used on raccoons in the Mount-Royal Park area. Vaccination campaigns may be expensive, but cost-benefit analysis suggests baits may be a cost-effective method of control. In Ontario , a dramatic drop in rabies was recorded when an aerial bait-vaccination campaign was launched. The number of recorded human deaths from rabies in the United States has dropped from 100 or more annually in the early 20th century to one or two per year due to widespread vaccination of domestic dogs and cats and the development of human vaccines and immunoglobulin treatments. Most deaths now result from bat bites, which may go unnoticed by the victim and hence untreated. Treatment after exposure can prevent the disease if given within 10 days. The rabies vaccine is 100% effective if given before symptoms of rabies appear. Every year, more than 15 million people get vaccinated after potential exposure. While this works well, the cost is significant. In the US it is recommended people receive one dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a 14-day period. HRIG is expensive and makes up most of the cost of post-exposure treatment, ranging as high as several thousand dollars. In the UK, one dose of HRIG costs the National Health Service £1,000, although this is not flagged as a "high-cost medication". A full course of vaccine costs £120–180. As much as possible of HRIG should be injected around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site. People who have previously been vaccinated against rabies do not need to receive the immunoglobulin—only the postexposure vaccinations on days 0 and 3. The side effects of modern cell-based vaccines are similar to the side effects of flu shots. The old nerve-tissue-based vaccination required multiple injections into the abdomen with a large needle but is inexpensive. It is being phased out and replaced by affordable World Health Organization intradermal-vaccination regimens. In children less than a year old, the lateral thigh is recommended. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is effective in reducing the number of viral particles. Povidone-iodine or alcohol is then recommended to reduce the virus further. Awakening to find a bat in the room, or finding a bat in the room of a previously unattended child or mentally disabled or intoxicated person, is an indication for post-exposure prophylaxis (PEP). The recommendation for the precautionary use of PEP in bat encounters where no contact is recognized has been questioned in the medical literature, based on a cost–benefit analysis . However, a 2002 study has supported the protocol of precautionary administration of PEP where a child or mentally compromised individual has been alone with a bat, especially in sleep areas, where a bite or exposure may occur with the victim being unaware. Once rabies develops, death almost certainly follows. Palliative care in a hospital setting is recommended with administration of large doses of pain medication, and sedatives in preference to physical restraint. Ice fragments can be given by mouth for thirst, but there is no good evidence intravenous hydration is of benefit. A treatment known as the Milwaukee protocol, which involves putting a person into a chemically induced coma and using antiviral medications , has been proposed. It initially came into use in 2003, following Jeanna Giese, a teenage girl from Wisconsin , becoming the first person known to have survived rabies without preventive treatments before symptom onset. The protocol has been tried multiple times since, but has been assessed as an ineffective treatment, and concerns raised about the costs and ethics of its use. Treatment after exposure can prevent the disease if given within 10 days. The rabies vaccine is 100% effective if given before symptoms of rabies appear. Every year, more than 15 million people get vaccinated after potential exposure. While this works well, the cost is significant. In the US it is recommended people receive one dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a 14-day period. HRIG is expensive and makes up most of the cost of post-exposure treatment, ranging as high as several thousand dollars. In the UK, one dose of HRIG costs the National Health Service £1,000, although this is not flagged as a "high-cost medication". A full course of vaccine costs £120–180. As much as possible of HRIG should be injected around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site. People who have previously been vaccinated against rabies do not need to receive the immunoglobulin—only the postexposure vaccinations on days 0 and 3. The side effects of modern cell-based vaccines are similar to the side effects of flu shots. The old nerve-tissue-based vaccination required multiple injections into the abdomen with a large needle but is inexpensive. It is being phased out and replaced by affordable World Health Organization intradermal-vaccination regimens. In children less than a year old, the lateral thigh is recommended. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is effective in reducing the number of viral particles. Povidone-iodine or alcohol is then recommended to reduce the virus further. Awakening to find a bat in the room, or finding a bat in the room of a previously unattended child or mentally disabled or intoxicated person, is an indication for post-exposure prophylaxis (PEP). The recommendation for the precautionary use of PEP in bat encounters where no contact is recognized has been questioned in the medical literature, based on a cost–benefit analysis . However, a 2002 study has supported the protocol of precautionary administration of PEP where a child or mentally compromised individual has been alone with a bat, especially in sleep areas, where a bite or exposure may occur with the victim being unaware. Once rabies develops, death almost certainly follows. Palliative care in a hospital setting is recommended with administration of large doses of pain medication, and sedatives in preference to physical restraint. Ice fragments can be given by mouth for thirst, but there is no good evidence intravenous hydration is of benefit. A treatment known as the Milwaukee protocol, which involves putting a person into a chemically induced coma and using antiviral medications , has been proposed. It initially came into use in 2003, following Jeanna Giese, a teenage girl from Wisconsin , becoming the first person known to have survived rabies without preventive treatments before symptom onset. The protocol has been tried multiple times since, but has been assessed as an ineffective treatment, and concerns raised about the costs and ethics of its use. Vaccination after exposure, PEP, is highly successful in preventing rabies. In unvaccinated humans, rabies is almost certainly fatal after neurological symptoms have developed. In 2010, an estimated 26,000 people died from rabies, down from 54,000 in 1990. The majority of the deaths occurred in Asia and Africa. As of 2015 [ update ] , India (approximately 20,847), followed by China (approximately 6,000) and the Democratic Republic of the Congo (5,600), had the most cases. A 2015 collaboration between the World Health Organization, World Organization of Animal Health (OIE), Food and Agriculture Organization of the United Nation (FAO), and Global Alliance for Rabies Control has a goal of eliminating deaths from rabies by 2030. India has the highest rate of human rabies in the world, primarily because of stray dogs, whose number has greatly increased since a 2001 law forbade the killing of dogs. Effective control and treatment of rabies in India is hindered by a form of mass hysteria known as puppy pregnancy syndrome (PPS). Dog bite victims with PPS, male as well as female, become convinced that puppies are growing inside them, and often seek help from faith healers rather than medical services. An estimated 20,000 people die every year from rabies in India, more than a third of the global total. Australia has an official rabies-free status, although Australian bat lyssavirus (ABLV), discovered in 1996, is a rabies-causing virus related to the rabies virus prevalent in Australian native bat populations. Canine-specific rabies has been eradicated in the United States, but rabies is common among wild animals, and an average of 100 dogs become infected from other wildlife each year. Due to high public awareness of the virus, efforts at vaccination of domestic animals and curtailment of feral populations, and availability of postexposure prophylaxis , incidence of rabies in humans is very rare in the United States. From 1960 to 2018, a total of 125 human rabies cases were reported in the United States; 36 (28%) were attributed to dog bites during international travel. Among the 89 infections acquired in the United States, 62 (70%) were attributed to bats. The most recent rabies death in the United States was in November 2021, where a Texas child was bitten by a bat in late August 2021 but his parents failed to get him treatment. He died less than three months later. Either no or very few cases of rabies are reported each year in Europe; cases are contracted both during travel and in Europe. In Switzerland the disease was virtually eliminated after scientists placed chicken heads laced with live attenuated vaccine in the Swiss Alps . Foxes, proven to be the main source of rabies in the country, ate the chicken heads and became immunized. Italy, after being declared rabies-free from 1997 to 2008, has witnessed a reemergence of the disease in wild animals in the Triveneto regions ( Trentino-Alto Adige/Südtirol , Veneto and Friuli Venezia Giulia ), due to the spreading of an epidemic in the Balkans that also affected Austria. An extensive wild animal vaccination campaign eliminated the virus from Italy again, and it regained the rabies-free country status in 2013, the last reported case of rabies being reported in a red fox in early 2011. The United Kingdom has been free of rabies since the early 20th century except for a rabies-like virus (EBLV-2) in a few Daubenton's bats . There has been one fatal case of EBLV-2 transmission to a human. There have been four deaths from rabies, transmitted abroad by dog bites, since 2000. The last infection in the UK occurred in 1922, and the last death from indigenous rabies was in 1902. Sweden and mainland Norway have been free of rabies since 1886. Bat rabies antibodies (but not the virus) have been found in bats. On Svalbard, animals can cross the arctic ice from Greenland or Russia. Mexico was certified by the World Health Organization as being free of dog-transmitted rabies in 2019 because no case of dog-human transmission had been recorded in two years. India has the highest rate of human rabies in the world, primarily because of stray dogs, whose number has greatly increased since a 2001 law forbade the killing of dogs. Effective control and treatment of rabies in India is hindered by a form of mass hysteria known as puppy pregnancy syndrome (PPS). Dog bite victims with PPS, male as well as female, become convinced that puppies are growing inside them, and often seek help from faith healers rather than medical services. An estimated 20,000 people die every year from rabies in India, more than a third of the global total. Australia has an official rabies-free status, although Australian bat lyssavirus (ABLV), discovered in 1996, is a rabies-causing virus related to the rabies virus prevalent in Australian native bat populations.Canine-specific rabies has been eradicated in the United States, but rabies is common among wild animals, and an average of 100 dogs become infected from other wildlife each year. Due to high public awareness of the virus, efforts at vaccination of domestic animals and curtailment of feral populations, and availability of postexposure prophylaxis , incidence of rabies in humans is very rare in the United States. From 1960 to 2018, a total of 125 human rabies cases were reported in the United States; 36 (28%) were attributed to dog bites during international travel. Among the 89 infections acquired in the United States, 62 (70%) were attributed to bats. The most recent rabies death in the United States was in November 2021, where a Texas child was bitten by a bat in late August 2021 but his parents failed to get him treatment. He died less than three months later. Either no or very few cases of rabies are reported each year in Europe; cases are contracted both during travel and in Europe. In Switzerland the disease was virtually eliminated after scientists placed chicken heads laced with live attenuated vaccine in the Swiss Alps . Foxes, proven to be the main source of rabies in the country, ate the chicken heads and became immunized. Italy, after being declared rabies-free from 1997 to 2008, has witnessed a reemergence of the disease in wild animals in the Triveneto regions ( Trentino-Alto Adige/Südtirol , Veneto and Friuli Venezia Giulia ), due to the spreading of an epidemic in the Balkans that also affected Austria. An extensive wild animal vaccination campaign eliminated the virus from Italy again, and it regained the rabies-free country status in 2013, the last reported case of rabies being reported in a red fox in early 2011. The United Kingdom has been free of rabies since the early 20th century except for a rabies-like virus (EBLV-2) in a few Daubenton's bats . There has been one fatal case of EBLV-2 transmission to a human. There have been four deaths from rabies, transmitted abroad by dog bites, since 2000. The last infection in the UK occurred in 1922, and the last death from indigenous rabies was in 1902. Sweden and mainland Norway have been free of rabies since 1886. Bat rabies antibodies (but not the virus) have been found in bats. On Svalbard, animals can cross the arctic ice from Greenland or Russia.Mexico was certified by the World Health Organization as being free of dog-transmitted rabies in 2019 because no case of dog-human transmission had been recorded in two years. Rabies has been known since around 2000 BC. The first written record of rabies is in the Mesopotamian Codex of Eshnunna ( c. 1930 BC ), which dictates that the owner of a dog showing symptoms of rabies should take preventive measures against bites. If another person were bitten by a rabid dog and later died, the owner was heavily fined. In Ancient Greece, rabies was supposed to be caused by Lyssa , the spirit of mad rage. Ineffective folk remedies abounded in the medical literature of the ancient world. The physician Scribonius Largus prescribed a poultice of cloth and hyena skin; Antaeus recommended a preparation made from the skull of a hanged man. Rabies appears to have originated in the Old World, the first epizootic in the New World occurring in Boston in 1768. Rabies was considered a scourge for its prevalence in the 19th century. In France and Belgium, where Saint Hubert was venerated, the " St Hubert's Key " was heated and applied to cauterize the wound. By an application of magical thinking , dogs were branded with the key in hopes of protecting them from rabies. It was not uncommon for a person bitten by a dog merely suspected of being rabid to commit suicide or to be killed by others. In ancient times the attachment of the tongue (the lingual frenulum , a mucous membrane) was cut and removed, as this was where rabies was thought to originate. This practice ceased with the discovery of the actual cause of rabies. Louis Pasteur's 1885 nerve tissue vaccine was successful, and was progressively improved to reduce often severe side-effects. In modern times, the fear of rabies has not diminished, and the disease and its symptoms, particularly agitation, have served as an inspiration for several works of zombie or similarly themed fiction, often portraying rabies as having mutated into a stronger virus which fills humans with murderous rage or incurable illness, bringing about a devastating, widespread pandemic. Rabies is infectious to mammals ; three stages of central nervous system infection are recognized. The clinical course is often shorter in animals than in humans, but result in similar symptoms and almost always death. The first stage is a one- to three-day period characterized by behavioral changes and is known as the prodromal stage . The second is the excitative stage, which lasts three to four days. This stage is often known as "furious rabies" for the tendency of the affected animal to be hyper-reactive to external stimuli and bite or attack anything near. In some cases, animals skip the excitative stage and develop paralysis, as in the third phase; the paralytic phase. This stage develops due to damage to motor neurons . Incoordination is seen, owing to rear limb paralysis , and drooling and difficulty swallowing is caused by paralysis of facial and throat muscles. Death is usually caused by respiratory arrest .

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Chikungunya

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Zika fever

Zika fever , also known as Zika virus disease or simply Zika , is an infectious disease caused by the Zika virus . Most cases have no symptoms, but when present they are usually mild and can resemble dengue fever . Symptoms may include fever , red eyes , joint pain , headache, and a maculopapular rash . Symptoms generally last less than seven days. It has not caused any reported deaths during the initial infection. Mother-to-child transmission during pregnancy can cause microcephaly and other brain malformations in some babies. Infections in adults have been linked to Guillain–Barré syndrome (GBS). Zika fever is mainly spread via the bite of mosquitoes of the Aedes type. It can also be sexually transmitted and potentially spread by blood transfusions . Infections in pregnant women can spread to the baby. Diagnosis is by testing the blood, urine, or saliva for the presence of the virus's RNA when the person is sick, or the blood for antibodies after symptoms are present more than a week. Prevention involves decreasing mosquito bites in areas where the disease occurs and proper use of condoms. Efforts to prevent bites include the use of insect repellent , covering much of the body with clothing, mosquito nets , and getting rid of standing water where mosquitoes reproduce. There is no effective vaccine . Health officials recommended that women in areas affected by the 2015–16 Zika outbreak consider putting off pregnancy and that pregnant women not travel to these areas. While there is no specific treatment, paracetamol (acetaminophen) may help with the symptoms. Admission to hospital is rarely necessary. The virus that causes the disease was first isolated in Africa in 1947. The first documented outbreak among people occurred in 2007 in the Federated States of Micronesia . An outbreak started in Brazil in 2015, and spread to the Americas, Pacific, Asia, and Africa. This led the World Health Organization to declare it a Public Health Emergency of International Concern in February 2016. The emergency was lifted in November 2016, but 84 countries still reported cases as of March 2017. The last proven case of Zika spread in the Continental United States was in 2017. Most people who are infected have no or few symptoms. Otherwise the most common signs and symptoms of Zika fever are fever , rash , conjunctivitis (red eyes), muscle and joint pain , and headache, which are similar to signs and symptoms of dengue and chikungunya fever. The time from a mosquito bite to developing symptoms is not yet known, but is probably a few days to a week. The disease lasts for several days to a week and is usually mild enough that people do not have to go to a hospital. Due to being in the same family as dengue, there has been concern that it could cause similar bleeding disorders. However that has only been documented in one case, with blood seen in semen, also known as hematospermia . Zika virus infections have been strongly associated with Guillain–Barré syndrome (GBS), which is a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system, and which can progress to paralysis. While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS. Though Zika virus has been shown to infect human Schwann cells . Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the 2013–2014 outbreak in French Polynesia there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak. The disease spreads from mother to child in the womb and can cause multiple problems, most notably microcephaly , in the baby. The full range of birth defects caused by infection during pregnancy is not known, but they appear to be common, with large scale abnormalities seen in up to 42% of live births. The most common observed associations have been abnormalities with brain and eye development such as microcephaly and chorioretinal scarring. Less commonly there have been systemic abnormalities such as hydrops fetalis , where there is abnormal accumulation of fluid in the fetus. These abnormalities can lead to intellectual problems, seizures , vision problems , hearing problems , problems feeding and slow development. Whether the stage of pregnancy at which the mother becomes infected affects the risk to the fetus is not well understood, nor is whether other risk factors affect outcomes. One group has estimated the risk of a baby developing microcephaly at about 1% when the mother is infected during the first trimester, with the risk of developing microcephaly becoming uncertain beyond the first trimester. Affected babies might appear normal but actually have brain abnormalities; infection in newborns could also lead to brain damage. Zika virus infections have been strongly associated with Guillain–Barré syndrome (GBS), which is a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system, and which can progress to paralysis. While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS. Though Zika virus has been shown to infect human Schwann cells . Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the 2013–2014 outbreak in French Polynesia there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak. The disease spreads from mother to child in the womb and can cause multiple problems, most notably microcephaly , in the baby. The full range of birth defects caused by infection during pregnancy is not known, but they appear to be common, with large scale abnormalities seen in up to 42% of live births. The most common observed associations have been abnormalities with brain and eye development such as microcephaly and chorioretinal scarring. Less commonly there have been systemic abnormalities such as hydrops fetalis , where there is abnormal accumulation of fluid in the fetus. These abnormalities can lead to intellectual problems, seizures , vision problems , hearing problems , problems feeding and slow development. Whether the stage of pregnancy at which the mother becomes infected affects the risk to the fetus is not well understood, nor is whether other risk factors affect outcomes. One group has estimated the risk of a baby developing microcephaly at about 1% when the mother is infected during the first trimester, with the risk of developing microcephaly becoming uncertain beyond the first trimester. Affected babies might appear normal but actually have brain abnormalities; infection in newborns could also lead to brain damage. Zika virus is a mosquito - borne flavivirus closely related to the dengue and yellow fever viruses. While mosquitoes are the vector , the main reservoir species remains unknown, though serological evidence has been found in both West African monkeys and rodents. Transmission is via the bite of mosquitoes from the genus Aedes , primarily Aedes aegypti in tropical regions. It has also been isolated from Ae. africanus , Ae. apicoargenteus , Ae. luteocephalus , Ae. albopictus , Ae. vittatus and Ae. furcifer . During the 2007 outbreak on Yap Island in the South Pacific, Aedes hensilli was the vector, while Aedes polynesiensis spread the virus in French Polynesia in 2013. Zika virus can also spread by sexual transmission from infected men to their partners. Zika virus has been isolated from semen samples, with one person having 100,000 times more virus in semen than blood or urine, two weeks after being infected. It is unclear why levels in semen can be higher than other body fluids, and it is also unclear how long infectious virus can remain in semen. There have also been cases of men with no symptoms of Zika virus infection transmitting the disease. The CDC has recommended that all men who have travelled to affected areas should wait at least 6 months before trying to attempt conception , regardless of whether they were ill. To date there have been no reported sexual transmissions from women to their sexual partners. Oral, anal or vaginal sex can spread the disease. Cases of vertical perinatal transmission have been reported. The CDC recommends that women with Zika fever should wait at least 8 weeks after they start having symptoms of disease before attempting to conceive. There have been no reported cases of transmission from breastfeeding, but infectious virus has been found in breast milk. Like other flaviviruses it could potentially be transmitted by blood transfusion and several affected countries have developed strategies to screen blood donors. The U.S. FDA has recommended universal screening of blood products for Zika. The virus is detected in 3% of asymptomatic blood donors in French Polynesia. Zika virus is a mosquito - borne flavivirus closely related to the dengue and yellow fever viruses. While mosquitoes are the vector , the main reservoir species remains unknown, though serological evidence has been found in both West African monkeys and rodents. Transmission is via the bite of mosquitoes from the genus Aedes , primarily Aedes aegypti in tropical regions. It has also been isolated from Ae. africanus , Ae. apicoargenteus , Ae. luteocephalus , Ae. albopictus , Ae. vittatus and Ae. furcifer . During the 2007 outbreak on Yap Island in the South Pacific, Aedes hensilli was the vector, while Aedes polynesiensis spread the virus in French Polynesia in 2013. Zika virus can also spread by sexual transmission from infected men to their partners. Zika virus has been isolated from semen samples, with one person having 100,000 times more virus in semen than blood or urine, two weeks after being infected. It is unclear why levels in semen can be higher than other body fluids, and it is also unclear how long infectious virus can remain in semen. There have also been cases of men with no symptoms of Zika virus infection transmitting the disease. The CDC has recommended that all men who have travelled to affected areas should wait at least 6 months before trying to attempt conception , regardless of whether they were ill. To date there have been no reported sexual transmissions from women to their sexual partners. Oral, anal or vaginal sex can spread the disease. Cases of vertical perinatal transmission have been reported. The CDC recommends that women with Zika fever should wait at least 8 weeks after they start having symptoms of disease before attempting to conceive. There have been no reported cases of transmission from breastfeeding, but infectious virus has been found in breast milk. Like other flaviviruses it could potentially be transmitted by blood transfusion and several affected countries have developed strategies to screen blood donors. The U.S. FDA has recommended universal screening of blood products for Zika. The virus is detected in 3% of asymptomatic blood donors in French Polynesia. In fruit flies microcephaly appears to be caused by the flavivirid virus protein NS4A , which can disrupt brain growth by hijacking a pathway which regulates growth of new neurons. It is difficult to diagnose Zika virus infection based on clinical signs and symptoms alone due to overlaps with other arboviruses that are endemic to similar areas. The US Centers for Disease Control and Prevention (CDC) advises that "based on the typical clinical features, the differential diagnosis for Zika virus infection is broad. In addition to dengue, other considerations include leptospirosis , malaria , rickettsia , group A streptococcus , rubella , measles , and parvovirus , enterovirus , adenovirus , and alphavirus infections (e.g., chikungunya, Mayaro , Ross River , Barmah Forest , O'nyong'nyong , and Sindbis viruses)." In small case series, routine chemistry and complete blood counts have been normal in most patients. A few have been reported to have mild leukopenia , thrombocytopenia , and elevated liver transaminases . Zika virus can be identified by reverse transcriptase PCR (RT-PCR) in acutely ill patients. However, the period of viremia can be short and the World Health Organization (WHO) recommends RT-PCR testing be done on serum collected within 1 to 3 days of symptom onset or on saliva samples collected during the first 3 to 5 days. When evaluating paired samples, Zika virus was detected more frequently in saliva than serum. Urine samples can be collected and tested up to 14 days after the onset of symptoms, as the virus has been seen to survive longer in the urine than either saliva or serum. The longest period of detectable virus has been 11 days and Zika virus does not appear to establish latency. Later on, serology for the detection of specific IgM and IgG antibodies to Zika virus can be used. IgM antibodies can be detectable within 3 days of the onset of illness. Serological cross-reactions with closely related flaviviruses such as dengue and West Nile virus as well as vaccines to flaviviruses are possible. As of 2019, the FDA has authorized two tests to detect Zika virus antibodies. The CDC recommends screening some pregnant women even if they do not have symptoms of infection. Pregnant women who have traveled to affected areas should be tested between two and twelve weeks after their return from travel. Due to the difficulties with ordering and interpreting tests for Zika virus, the CDC also recommends that healthcare providers contact their local health department for assistance. For women living in affected areas, the CDC has recommended testing at the first prenatal visit with a doctor as well as in the mid-second trimester , though this may be adjusted based on local resources and the local burden of Zika virus. Additional testing should be done if there are any signs of Zika virus disease. Women with positive test results for Zika virus infection should have their fetus monitored by ultrasound every three to four weeks to monitor fetal anatomy and growth. For infants with suspected congenital Zika virus disease, the CDC recommends testing with both serologic and molecular assays such as RT-PCR, IgM ELISA and plaque reduction neutralization test (PRNT). RT-PCR of the infants serum and urine should be performed in the first two days of life. Newborns with a mother who was potentially exposed and who have positive blood tests, microcephaly or intracranial calcifications should have further testing including a thorough physical investigation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions. Other recommended tests are cranial ultrasound, hearing evaluation, and eye examination. Testing should be done for any abnormalities encountered as well as for other congenital infections such as syphilis , toxoplasmosis , rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, and herpes simplex virus . Some tests should be repeated up to 6 months later as there can be delayed effects, particularly with hearing. In response to the widespread transmission of Zika virus during the 2016 outbreak and concerns of viral genetic material detected in breast milk the World Health Organization (WHO) released a Guideline of infant feeding in areas of Zika virus transmission, first in 2016 and updated in 2021, where the evidence showed that despite the detection of Zika virus in breast milk, there is unclear evidence of transmission to the infant, and considering that Zika virus infection among infants is mild, the balance between desirable and undesirable effects favours breastfeeding versus not breastfeeding. According to the 2021WHO guidelines: The CDC recommends screening some pregnant women even if they do not have symptoms of infection. Pregnant women who have traveled to affected areas should be tested between two and twelve weeks after their return from travel. Due to the difficulties with ordering and interpreting tests for Zika virus, the CDC also recommends that healthcare providers contact their local health department for assistance. For women living in affected areas, the CDC has recommended testing at the first prenatal visit with a doctor as well as in the mid-second trimester , though this may be adjusted based on local resources and the local burden of Zika virus. Additional testing should be done if there are any signs of Zika virus disease. Women with positive test results for Zika virus infection should have their fetus monitored by ultrasound every three to four weeks to monitor fetal anatomy and growth. For infants with suspected congenital Zika virus disease, the CDC recommends testing with both serologic and molecular assays such as RT-PCR, IgM ELISA and plaque reduction neutralization test (PRNT). RT-PCR of the infants serum and urine should be performed in the first two days of life. Newborns with a mother who was potentially exposed and who have positive blood tests, microcephaly or intracranial calcifications should have further testing including a thorough physical investigation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions. Other recommended tests are cranial ultrasound, hearing evaluation, and eye examination. Testing should be done for any abnormalities encountered as well as for other congenital infections such as syphilis , toxoplasmosis , rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, and herpes simplex virus . Some tests should be repeated up to 6 months later as there can be delayed effects, particularly with hearing. In response to the widespread transmission of Zika virus during the 2016 outbreak and concerns of viral genetic material detected in breast milk the World Health Organization (WHO) released a Guideline of infant feeding in areas of Zika virus transmission, first in 2016 and updated in 2021, where the evidence showed that despite the detection of Zika virus in breast milk, there is unclear evidence of transmission to the infant, and considering that Zika virus infection among infants is mild, the balance between desirable and undesirable effects favours breastfeeding versus not breastfeeding. According to the 2021WHO guidelines: The virus is spread by mosquitoes, making mosquito avoidance an important element to disease control. The CDC recommends that individuals: The CDC also recommends strategies for controlling mosquitoes such as eliminating standing water, repairing septic tanks and using screens on doors and windows. Spraying insecticide is used to kill flying mosquitoes and larvicide can be used in water containers. Because Zika virus can be sexually transmitted, men who have gone to an area where Zika fever is occurring should be counseled to either abstain from sex or use condoms for 6 months after travel if their partner is pregnant or could potentially become pregnant. Breastfeeding is still recommended by the WHO, even by women who have had Zika fever. There have been no recorded cases of Zika transmission to infants through breastfeeding, though the replicative virus has been detected in breast milk. When returning from travel, with or without symptoms, it is suggested that prevention of mosquito bites continue for 3 weeks in order reduce the risk of virus transmission to uninfected mosquitos. Because of the "growing evidence of a link between Zika and microcephaly", in January 2016, the CDC issued a travel alert advising pregnant women to consider postponing travel to countries and territories with ongoing local transmission of Zika virus. Later, the advice was updated to caution pregnant women to avoid these areas entirely if possible and, if travel is unavoidable, to protect themselves from mosquito bites. Male partners of pregnant women and couples contemplating pregnancy who must travel to areas where Zika is active are advised to use condoms or abstain from sex. The agency also suggested that women thinking about becoming pregnant should consult with their physicians before traveling. In September 2016, the CDC travel advisories included: Cape Verde Many parts of the Caribbean: Anguilla, Antigua and Barbuda, Aruba, The Bahamas, Barbados, Bonaire, British Virgin Islands, Cayman Islands, Cuba, Curaçao, Dominica, Dominican Republic, Grenada, Guadeloupe, Haiti, Jamaica, Martinique, Puerto Rico, Saba, Saint Saint Barthélemy, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, Sint Eustatius, Sint Maarten, Trinidad and Tobago, and the U.S. Virgin Islands Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama Mexico Most of South America: Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Peru, Suriname, and Venezuela Several Pacific Islands: American Samoa, Fiji, Marshall Islands, Micronesia, New Caledonia, Papua New Guinea, Samoa, and Tonga In Asia: Singapore, Malaysia, Brunei In December 2020, no active Zika outbreaks were reported by the CDC. Both the regional Pan American Health Organization (PAHO) as well as the WHO have issued statements of concern about the widespread public health impact of the Zika virus and its links to GBS and microcephaly. The WHO Director-General, Margaret Chan , issued a statement in February 2016 "declaring that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern." The declaration allowed the WHO to coordinate international response to the virus as well as gave its guidance the force of international law under the International Health Regulations . The declaration was ended in November 2016. As of 2016 there was no available vaccine. Development was a priority of the US National Institutes of Health (NIH), but officials stated that development of a vaccine could take years. To speed new drug development regulatory strategies were proposed by the WHO and NIH. Animal and early human studies were underway as of September 2016. As of December 2019, there were several vaccine candidates in various stages of development. Disease control in the affected countries currently centres around mosquito control. Several approaches are available for the management of Aedes aegypti mosquito populations, including the destruction of larval breeding sites (the aquatic pools in which eggs are laid and larvae hatch prior to mosquito development into flying adults); and, insecticides targeting either the larval stages, adult mosquitoes or both. Additionally, a whole host of novel technologies are under current development for mosquito control and the World Health Organization has recently lent its support for the accelerated development of modern methods for mosquito control such as the use of Wolbachia bacteria to render mosquitoes resistant to the virus, and, the release of sterilized male mosquitoes that breed with wild female mosquitoes to give rise to non-viable offspring (offspring that do not survive to the biting, adult stage). Oxitec 's genetically modified OX513A mosquito was approved by Brazil's National Biosecurity Technical Commission (CTNBio) in April 2014 and it was being used to try to combat mosquitoes carrying the Zika virus in the town of Piracicaba , São Paulo in 2016. In the 1940s and 1950s, the Aedes aegypti mosquito was eradicated on some Caribbean islands and in at least eighteen Latin American countries. Decreasing political will and presumably available money, mosquito resistance to insecticide, and a pace of urbanization which exceeded eradication efforts led to this mosquito's comeback. Because of the "growing evidence of a link between Zika and microcephaly", in January 2016, the CDC issued a travel alert advising pregnant women to consider postponing travel to countries and territories with ongoing local transmission of Zika virus. Later, the advice was updated to caution pregnant women to avoid these areas entirely if possible and, if travel is unavoidable, to protect themselves from mosquito bites. Male partners of pregnant women and couples contemplating pregnancy who must travel to areas where Zika is active are advised to use condoms or abstain from sex. The agency also suggested that women thinking about becoming pregnant should consult with their physicians before traveling. In September 2016, the CDC travel advisories included: Cape Verde Many parts of the Caribbean: Anguilla, Antigua and Barbuda, Aruba, The Bahamas, Barbados, Bonaire, British Virgin Islands, Cayman Islands, Cuba, Curaçao, Dominica, Dominican Republic, Grenada, Guadeloupe, Haiti, Jamaica, Martinique, Puerto Rico, Saba, Saint Saint Barthélemy, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, Sint Eustatius, Sint Maarten, Trinidad and Tobago, and the U.S. Virgin Islands Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama Mexico Most of South America: Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Peru, Suriname, and Venezuela Several Pacific Islands: American Samoa, Fiji, Marshall Islands, Micronesia, New Caledonia, Papua New Guinea, Samoa, and Tonga In Asia: Singapore, Malaysia, Brunei In December 2020, no active Zika outbreaks were reported by the CDC. Both the regional Pan American Health Organization (PAHO) as well as the WHO have issued statements of concern about the widespread public health impact of the Zika virus and its links to GBS and microcephaly. The WHO Director-General, Margaret Chan , issued a statement in February 2016 "declaring that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern." The declaration allowed the WHO to coordinate international response to the virus as well as gave its guidance the force of international law under the International Health Regulations . The declaration was ended in November 2016. As of 2016 there was no available vaccine. Development was a priority of the US National Institutes of Health (NIH), but officials stated that development of a vaccine could take years. To speed new drug development regulatory strategies were proposed by the WHO and NIH. Animal and early human studies were underway as of September 2016. As of December 2019, there were several vaccine candidates in various stages of development. Disease control in the affected countries currently centres around mosquito control. Several approaches are available for the management of Aedes aegypti mosquito populations, including the destruction of larval breeding sites (the aquatic pools in which eggs are laid and larvae hatch prior to mosquito development into flying adults); and, insecticides targeting either the larval stages, adult mosquitoes or both. Additionally, a whole host of novel technologies are under current development for mosquito control and the World Health Organization has recently lent its support for the accelerated development of modern methods for mosquito control such as the use of Wolbachia bacteria to render mosquitoes resistant to the virus, and, the release of sterilized male mosquitoes that breed with wild female mosquitoes to give rise to non-viable offspring (offspring that do not survive to the biting, adult stage). Oxitec 's genetically modified OX513A mosquito was approved by Brazil's National Biosecurity Technical Commission (CTNBio) in April 2014 and it was being used to try to combat mosquitoes carrying the Zika virus in the town of Piracicaba , São Paulo in 2016. In the 1940s and 1950s, the Aedes aegypti mosquito was eradicated on some Caribbean islands and in at least eighteen Latin American countries. Decreasing political will and presumably available money, mosquito resistance to insecticide, and a pace of urbanization which exceeded eradication efforts led to this mosquito's comeback. There is currently no specific treatment for Zika virus infection. Care is supportive with treatment of pain, fever, and itching. Some authorities have recommended against using aspirin and other NSAIDs as these have been associated with hemorrhagic syndrome when used for other flaviviruses. Additionally, aspirin use is generally avoided in children when possible due to the risk of Reye syndrome . Zika virus had been relatively little studied until the major outbreak in 2015, and no specific antiviral treatments are available as yet. Advice to pregnant women is to avoid any risk of infection so far as possible, as once infected there is little that can be done beyond supportive treatment. Most of the time, Zika fever resolves on its own in two to seven days, but rarely, some people develop Guillain–Barré syndrome . The fetus of a pregnant woman who has Zika fever may die or be born with congenital central nervous system malformations, like microcephaly . In April 1947, as part of studies sponsored by the Rockefeller Foundation into yellow fever , 6 caged rhesus monkeys were placed in the canopy of the Zika Forest of Uganda. On April 18 one of the monkeys (no. 776) developed a fever and blood samples revealed the first known case of Zika fever. Population surveys at the time in Uganda found 6.1% of individuals to be seropositive for Zika. The first human cases were reported in Nigeria in 1954. A few outbreaks have been reported in tropical Africa and in some areas in Southeast Asia. Until recently there were no documented cases of Zika virus in the Indian subcontinent , however, the first cases were reported in 2017 from Gujarat state and Tamil Nadu, more cases were reported in Rajasthan state involving an outbreak of 153 reported cases and in a pregnant women living in Kerala state. A 1954 study assessing blood samples from several people from different states found antibodies to Zika in healthy people in India which could indicate past exposure, though it could also be due to cross-reaction with other flaviviruses. By using phylogenetic analysis of Asian strains, it was estimated that Zika virus had moved to Southeast Asia by 1945. In 1977–1978, Zika virus infection was described as a cause of fever in Indonesia. Before 2007, there were only 13 reported natural infections with Zika virus, all with a mild, self-limited febrile illness. As of July 2019, evidence of local transmission from mosquitoes to humans has been reported in a total of 87 countries from four of six WHO Regions ; African, Americas, South-East Asia and Western Pacific. The first major outbreak, with 185 confirmed cases, was reported in 2007 in the Yap Islands of the Federated States of Micronesia. A total of 108 cases were confirmed by PCR or serology and 72 additional cases were suspected. The most common symptoms were rash, fever, arthralgia, and conjunctivitis, and no deaths were reported. The mosquito Aedes hensilli , which was the predominant species identified in Yap during the outbreak, was probably the main vector of transmission. While the way of introduction of the virus on Yap Island remains uncertain, it is likely to have happened through introduction of infected mosquitoes or a human infected with a strain related to those in Southeast Asia. This was also the first time Zika fever had been reported outside Africa and Asia. Before the Yap Island outbreak, only 14 human cases had ever been reported. In 2013–2014, several outbreaks of Zika were reported in French Polynesia , New Caledonia , Easter Island and the Cook Islands . The source of the virus was thought to be an independent introduction of the virus from Southeast Asia , unrelated to the Yap Islands outbreak. Genetic analyses of Zika virus strains suggest that Zika first entered the Americas between May and December 2013. It was first detected in the Western Hemisphere in February 2014, and rapidly spread throughout South and Central America, reaching Mexico in November 2015. In 2016 it established local transmission in Florida and Texas. The first death in the United States due to Zika occurred in February 2016. In May 2015, Brazil officially reported its first 16 cases of the illness. Although, a case of illness was reported in March 2015 in a returning traveller. According to the Brazilian Health Ministry, as of November 2015 there was no official count of the number of people infected with the virus in Brazil, since the disease is not subject to compulsory notification. Even so, cases were reported in 14 states of the country. Mosquito-borne Zika virus is suspected to be the cause of 2,400 possible cases of microcephaly and 29 infant deaths in Brazil in 2015 (of the 2400 or so notified cases in 2015, 2165 were under investigation in December 2015, 134 were confirmed and 102 were ruled out for microcephaly). The Brazilian Health Ministry has reported at least 2,400 suspected cases of microcephaly in the country in 2015 as of 12 December, and 29 fatalities. Before the Zika outbreak, only an average of 150 to 200 cases per year were reported in Brazil. In the state of Pernambuco the reported rates of microcephaly in 2015 are 77 times higher than in the previous 5 years. A model using data from a Zika outbreak in French Polynesia estimated the risk of microcephaly in children born to mothers who acquired Zika virus in the first trimester to be 1%. On 24 January 2016, the WHO warned that the virus is likely to spread to nearly all countries of the Americas, since its vector, the mosquito Aedes aegypti , is found in all countries in the region, except for Canada and continental Chile . The mosquito and dengue fever have been detected in Chile's Easter Island, some 3,500 km (2,200 mi) away from its closest point in mainland Chile, since 2002. In February 2016, WHO declared the outbreak a Public Health Emergency of International Concern as evidence grew that Zika is a cause of birth defects and neurological problems. In April 2016, WHO stated there is a scientific consensus, based on preliminary evidence, that Zika is a cause of microcephaly in infants and Guillain–Barré syndrome in adults. Studies of this and prior outbreaks have found Zika infection during pregnancy to be associated with early pregnancy loss and other pregnancy problems. In the Americas the number of cases peaked during the first half of 2016 and declined through 2017–2018, with a total of 31,587 suspected, probable, and confirmed cases of ZIKV disease were reported in the Region of the Americas. Of these, 3,473 (11%) were laboratory confirmed. In general, transmission persists at low levels in some areas and is not uniformly distributed within countries. In 2016 imported or locally transmitted Zika was reported in all the countries of Asia except Brunei, Hong Kong, Myanmar and Nepal. Serological surveys have indicated that Zika virus is endemic in most areas of Asia, though at a low level. While there was a sharp rise in the number of cases of Zika detected in Singapore after the 2016 Summer Olympics in Brazil, genetic analysis revealed that the strains were more closely related to strains from Thailand than from those causing the epidemic in the Americas. The first major outbreak, with 185 confirmed cases, was reported in 2007 in the Yap Islands of the Federated States of Micronesia. A total of 108 cases were confirmed by PCR or serology and 72 additional cases were suspected. The most common symptoms were rash, fever, arthralgia, and conjunctivitis, and no deaths were reported. The mosquito Aedes hensilli , which was the predominant species identified in Yap during the outbreak, was probably the main vector of transmission. While the way of introduction of the virus on Yap Island remains uncertain, it is likely to have happened through introduction of infected mosquitoes or a human infected with a strain related to those in Southeast Asia. This was also the first time Zika fever had been reported outside Africa and Asia. Before the Yap Island outbreak, only 14 human cases had ever been reported. In 2013–2014, several outbreaks of Zika were reported in French Polynesia , New Caledonia , Easter Island and the Cook Islands . The source of the virus was thought to be an independent introduction of the virus from Southeast Asia , unrelated to the Yap Islands outbreak. Genetic analyses of Zika virus strains suggest that Zika first entered the Americas between May and December 2013. It was first detected in the Western Hemisphere in February 2014, and rapidly spread throughout South and Central America, reaching Mexico in November 2015. In 2016 it established local transmission in Florida and Texas. The first death in the United States due to Zika occurred in February 2016. In May 2015, Brazil officially reported its first 16 cases of the illness. Although, a case of illness was reported in March 2015 in a returning traveller. According to the Brazilian Health Ministry, as of November 2015 there was no official count of the number of people infected with the virus in Brazil, since the disease is not subject to compulsory notification. Even so, cases were reported in 14 states of the country. Mosquito-borne Zika virus is suspected to be the cause of 2,400 possible cases of microcephaly and 29 infant deaths in Brazil in 2015 (of the 2400 or so notified cases in 2015, 2165 were under investigation in December 2015, 134 were confirmed and 102 were ruled out for microcephaly). The Brazilian Health Ministry has reported at least 2,400 suspected cases of microcephaly in the country in 2015 as of 12 December, and 29 fatalities. Before the Zika outbreak, only an average of 150 to 200 cases per year were reported in Brazil. In the state of Pernambuco the reported rates of microcephaly in 2015 are 77 times higher than in the previous 5 years. A model using data from a Zika outbreak in French Polynesia estimated the risk of microcephaly in children born to mothers who acquired Zika virus in the first trimester to be 1%. On 24 January 2016, the WHO warned that the virus is likely to spread to nearly all countries of the Americas, since its vector, the mosquito Aedes aegypti , is found in all countries in the region, except for Canada and continental Chile . The mosquito and dengue fever have been detected in Chile's Easter Island, some 3,500 km (2,200 mi) away from its closest point in mainland Chile, since 2002. In February 2016, WHO declared the outbreak a Public Health Emergency of International Concern as evidence grew that Zika is a cause of birth defects and neurological problems. In April 2016, WHO stated there is a scientific consensus, based on preliminary evidence, that Zika is a cause of microcephaly in infants and Guillain–Barré syndrome in adults. Studies of this and prior outbreaks have found Zika infection during pregnancy to be associated with early pregnancy loss and other pregnancy problems. In the Americas the number of cases peaked during the first half of 2016 and declined through 2017–2018, with a total of 31,587 suspected, probable, and confirmed cases of ZIKV disease were reported in the Region of the Americas. Of these, 3,473 (11%) were laboratory confirmed. In general, transmission persists at low levels in some areas and is not uniformly distributed within countries. In 2016 imported or locally transmitted Zika was reported in all the countries of Asia except Brunei, Hong Kong, Myanmar and Nepal. Serological surveys have indicated that Zika virus is endemic in most areas of Asia, though at a low level. While there was a sharp rise in the number of cases of Zika detected in Singapore after the 2016 Summer Olympics in Brazil, genetic analysis revealed that the strains were more closely related to strains from Thailand than from those causing the epidemic in the Americas. It is named after the Zika Forest near Entebbe , Uganda , where the Zika virus was first identified. Zika virus was first identified in the late 1940s in Kampala, Uganda, Africa but was first confirmed in Brazil. Since it was first identified, Zika has been found in more than 27 countries and territories. Following the initial Zika outbreak in Northeastern Brazil in May 2015, physicians observed a very large surge of reports of infants born with microcephaly , with 20 times the number of expected cases. Many of these cases have since been confirmed, leading WHO officials to project that approximately 2,500 infants will be found to have born in Brazil with Zika-related microcephaly. Proving that Zika causes these effects was difficult and complex for several reasons. For example, the effects on an infant might not be seen until months after the mother's initial infection, long after the time when Zika is easily detected in the body. In addition, research was needed to determine the mechanism by which Zika produced these effects. Since the initial outbreak, studies that use several different methods found evidence of a link, leading public health officials to conclude that it appears increasingly likely the virus is linked to microcephaly and miscarriage. On 1 February 2016, the World Health Organization declared recently reported clusters of microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC). On 8 March 2016, the WHO Committee reconfirmed that the association between Zika and neurological disorders is of global concern. The Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak. In 2015, there were 2,782 suspected cases of microcephaly compared with 147 in 2014 and 167 in 2013. Confirmation of many of the recent cases is pending, and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections. In November 2015, the Zika virus was isolated in a newborn baby from the northeastern state of Ceará , Brazil, with microcephaly and other congenital disorders . The Lancet medical journal reported in January 2016 that the Brazilian Ministry of Health had confirmed 134 cases of microcephaly "believed to be associated with Zika virus infection" with an additional 2,165 cases in 549 counties in 20 states remaining under investigation. An analysis of 574 cases of microcephaly in Brazil during 2015 and the first week of 2016, reported in March 2016, found an association with maternal illness involving rash and fever during the first trimester of pregnancy. During this period, 12 Brazilian states reported increases of at least 3 standard deviations (SDs) in cases of microcephaly compared with 2000–14, with the northeastern states of Bahia, Paraíba and Pernambuco reporting increases of more than 20 SDs. In January 2016, a baby in Oahu , Hawaii, was born with microcephaly, the first case in the United States of brain damage linked to the virus. The baby and mother tested positive for a past Zika virus infection. The mother, who had probably acquired the virus while traveling in Brazil in May 2015 during the early stages of her pregnancy, had reported her bout of Zika. She recovered before relocating to Hawaii. Her pregnancy had progressed normally, and the baby's condition was not known until birth. In February 2016, ocular disorders in newborns have been linked to Zika virus infection. In one study in Pernambuco state in Brazil, about 40 percent of babies with Zika-related microcephaly also had scarring of the retina with spots, or pigment alteration . On 20 February 2016, Brazilian scientists announced that they had successfully sequenced the Zika virus genome and expressed hope that this would help in both developing a vaccine and in determining the nature of any link to birth defects. Also in February 2016, rumors that microcephaly is caused by the use of the larvicide pyriproxyfen in drinking water were refuted by scientists. "It's important to state that some localities that do not use pyriproxyfen also had reported cases of microcephaly", read a Brazilian government statement. The Brazilian government also refuted conspiracy theories that chickenpox and rubella vaccinations or genetically modified mosquitoes were causing increases in microcephaly. Researchers also suspected that Zika virus could be transmitted by a pregnant woman to her baby (" vertical transmission "). This remained unproven until February 2016, when a paper by Calvet et al. was published, showing not only was the Zika virus genome found in the amniotic fluid but also IgM antibodies against the virus. This means that not only can the virus cross the placental barrier, but also the antibodies produced by the mother can reach the fetus, which suggests that vertical transmission is plausible in these cases. One other study published in March 2016 by Mlakar and colleagues analyzed autopsy tissues from a fetus with microcephaly that was probably related to Zika virus; researchers found ZIKV in the brain tissue and suggested that the brain injuries were probably associated with the virus, which also shed a light on the vertical transmission theory. Also in March 2016, first solid evidence was reported on how the virus affects the development of the brain, indicating that it appears to preferentially kill developing brain cells. The first cases of birth defects linked to Zika in Colombia and in Panama were reported in March 2016. In the same month, researchers published a prospective cohort study that found profound impacts in 29 percent of infants of mothers infected with Zika, some of whom were infected late in pregnancy. This study did not suffer from some of the difficulties of studying Zika: the study followed women who presented to a Rio de Janeiro clinic with fever and rash within the last five days. The women were then tested for Zika using PCR, then the progress of the pregnancies were followed using ultrasound. A high rate of the autoimmune disease Guillain–Barré syndrome (GBS), noted in the French Polynesia outbreak, has also been found in the outbreak that began in Brazil. Laboratory analysis found Zika infections in some patients with GBS in Brazil, El Salvador, Suriname and Venezuela, and the WHO declared on 22 March 2016 that Zika appeared to be "implicated" in GBS infection and that if the pattern was confirmed it would represent a global public health crisis. It is named after the Zika Forest near Entebbe , Uganda , where the Zika virus was first identified. Zika virus was first identified in the late 1940s in Kampala, Uganda, Africa but was first confirmed in Brazil. Since it was first identified, Zika has been found in more than 27 countries and territories. Following the initial Zika outbreak in Northeastern Brazil in May 2015, physicians observed a very large surge of reports of infants born with microcephaly , with 20 times the number of expected cases. Many of these cases have since been confirmed, leading WHO officials to project that approximately 2,500 infants will be found to have born in Brazil with Zika-related microcephaly. Proving that Zika causes these effects was difficult and complex for several reasons. For example, the effects on an infant might not be seen until months after the mother's initial infection, long after the time when Zika is easily detected in the body. In addition, research was needed to determine the mechanism by which Zika produced these effects. Since the initial outbreak, studies that use several different methods found evidence of a link, leading public health officials to conclude that it appears increasingly likely the virus is linked to microcephaly and miscarriage. On 1 February 2016, the World Health Organization declared recently reported clusters of microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC). On 8 March 2016, the WHO Committee reconfirmed that the association between Zika and neurological disorders is of global concern. The Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak. In 2015, there were 2,782 suspected cases of microcephaly compared with 147 in 2014 and 167 in 2013. Confirmation of many of the recent cases is pending, and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections. In November 2015, the Zika virus was isolated in a newborn baby from the northeastern state of Ceará , Brazil, with microcephaly and other congenital disorders . The Lancet medical journal reported in January 2016 that the Brazilian Ministry of Health had confirmed 134 cases of microcephaly "believed to be associated with Zika virus infection" with an additional 2,165 cases in 549 counties in 20 states remaining under investigation. An analysis of 574 cases of microcephaly in Brazil during 2015 and the first week of 2016, reported in March 2016, found an association with maternal illness involving rash and fever during the first trimester of pregnancy. During this period, 12 Brazilian states reported increases of at least 3 standard deviations (SDs) in cases of microcephaly compared with 2000–14, with the northeastern states of Bahia, Paraíba and Pernambuco reporting increases of more than 20 SDs. In January 2016, a baby in Oahu , Hawaii, was born with microcephaly, the first case in the United States of brain damage linked to the virus. The baby and mother tested positive for a past Zika virus infection. The mother, who had probably acquired the virus while traveling in Brazil in May 2015 during the early stages of her pregnancy, had reported her bout of Zika. She recovered before relocating to Hawaii. Her pregnancy had progressed normally, and the baby's condition was not known until birth. In February 2016, ocular disorders in newborns have been linked to Zika virus infection. In one study in Pernambuco state in Brazil, about 40 percent of babies with Zika-related microcephaly also had scarring of the retina with spots, or pigment alteration . On 20 February 2016, Brazilian scientists announced that they had successfully sequenced the Zika virus genome and expressed hope that this would help in both developing a vaccine and in determining the nature of any link to birth defects. Also in February 2016, rumors that microcephaly is caused by the use of the larvicide pyriproxyfen in drinking water were refuted by scientists. "It's important to state that some localities that do not use pyriproxyfen also had reported cases of microcephaly", read a Brazilian government statement. The Brazilian government also refuted conspiracy theories that chickenpox and rubella vaccinations or genetically modified mosquitoes were causing increases in microcephaly. Researchers also suspected that Zika virus could be transmitted by a pregnant woman to her baby (" vertical transmission "). This remained unproven until February 2016, when a paper by Calvet et al. was published, showing not only was the Zika virus genome found in the amniotic fluid but also IgM antibodies against the virus. This means that not only can the virus cross the placental barrier, but also the antibodies produced by the mother can reach the fetus, which suggests that vertical transmission is plausible in these cases. One other study published in March 2016 by Mlakar and colleagues analyzed autopsy tissues from a fetus with microcephaly that was probably related to Zika virus; researchers found ZIKV in the brain tissue and suggested that the brain injuries were probably associated with the virus, which also shed a light on the vertical transmission theory. Also in March 2016, first solid evidence was reported on how the virus affects the development of the brain, indicating that it appears to preferentially kill developing brain cells. The first cases of birth defects linked to Zika in Colombia and in Panama were reported in March 2016. In the same month, researchers published a prospective cohort study that found profound impacts in 29 percent of infants of mothers infected with Zika, some of whom were infected late in pregnancy. This study did not suffer from some of the difficulties of studying Zika: the study followed women who presented to a Rio de Janeiro clinic with fever and rash within the last five days. The women were then tested for Zika using PCR, then the progress of the pregnancies were followed using ultrasound. A high rate of the autoimmune disease Guillain–Barré syndrome (GBS), noted in the French Polynesia outbreak, has also been found in the outbreak that began in Brazil. Laboratory analysis found Zika infections in some patients with GBS in Brazil, El Salvador, Suriname and Venezuela, and the WHO declared on 22 March 2016 that Zika appeared to be "implicated" in GBS infection and that if the pattern was confirmed it would represent a global public health crisis. Early in the 2015–16 Zika virus epidemic , research was begun to better understand how Zika virus causes microcephaly and other neurological disorders. However, with the 2019 election of Jair Bolsonaro in Brazil, who cut funding for research, and the emergence of the COVID-19 pandemic in early 2020, most Zika-related research projects were abandoned or reduced. It may involve infection of the primary neural stem cells of the fetal brain, known as neural progenitor cells. The main roles of brain stem cells are to proliferate until the correct number is achieved, and then to produce neurons through the process of neurogenesis . Zika proteins NS4A and NS4B have also been shown to directly suppress neurogenesis. Infection of brain stem cells can cause cell death, which reduces the production of future neurons and leads to a smaller brain. Zika also appears to have an equal tropism for cells of the developing eye, leading to high rates of eye abnormalities as well. In addition to inducing cell death, infection of neural progenitor cells may alter the process of cell proliferation, causing a depletion in the pool of progenitor cells. A large number of cases of microcephaly have been associated with inherited gene mutations, and specifically with mutations that lead to dysfunction of the mitotic spindle . There is some evidence that Zika virus may directly or indirectly interfere with mitotic function, this may play a role in altering cell proliferation. Another line of research considers that Zika, unlike other flaviviruses, may target developing brain cells after it crosses the placenta, and considers the resulting damage likely to be the result of inflammation as a byproduct of the immune response to the infection of those cells. Some experimental methods of prevention include breeding and releasing mosquitoes that have been genetically modified to prevent them from transmitting pathogens, or have been infected with the Wolbachia bacterium, believed to inhibit the spread of viruses. A strain of Wolbachia helped to reduce the vector competence of the Zika virus in infected Aedes aegypti released in Medellin, Colombia. Gene drive is a technique for changing wild populations, for instance to combat insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria and Zika). Another method which been researched aims to render male mosquitoes infertile by nuclear radiation in the hope to reduce populations; this is done with a cobalt-60 gamma cell irradiator. In 2016 the World Health Organization encouraged field trials of transgenic male Aedes aegypti mosquitoes developed by Oxitec to try to halt the spread of the Zika virus. Early in the 2015–16 Zika virus epidemic , research was begun to better understand how Zika virus causes microcephaly and other neurological disorders. However, with the 2019 election of Jair Bolsonaro in Brazil, who cut funding for research, and the emergence of the COVID-19 pandemic in early 2020, most Zika-related research projects were abandoned or reduced. It may involve infection of the primary neural stem cells of the fetal brain, known as neural progenitor cells. The main roles of brain stem cells are to proliferate until the correct number is achieved, and then to produce neurons through the process of neurogenesis . Zika proteins NS4A and NS4B have also been shown to directly suppress neurogenesis. Infection of brain stem cells can cause cell death, which reduces the production of future neurons and leads to a smaller brain. Zika also appears to have an equal tropism for cells of the developing eye, leading to high rates of eye abnormalities as well. In addition to inducing cell death, infection of neural progenitor cells may alter the process of cell proliferation, causing a depletion in the pool of progenitor cells. A large number of cases of microcephaly have been associated with inherited gene mutations, and specifically with mutations that lead to dysfunction of the mitotic spindle . There is some evidence that Zika virus may directly or indirectly interfere with mitotic function, this may play a role in altering cell proliferation. Another line of research considers that Zika, unlike other flaviviruses, may target developing brain cells after it crosses the placenta, and considers the resulting damage likely to be the result of inflammation as a byproduct of the immune response to the infection of those cells. Some experimental methods of prevention include breeding and releasing mosquitoes that have been genetically modified to prevent them from transmitting pathogens, or have been infected with the Wolbachia bacterium, believed to inhibit the spread of viruses. A strain of Wolbachia helped to reduce the vector competence of the Zika virus in infected Aedes aegypti released in Medellin, Colombia. Gene drive is a technique for changing wild populations, for instance to combat insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria and Zika). Another method which been researched aims to render male mosquitoes infertile by nuclear radiation in the hope to reduce populations; this is done with a cobalt-60 gamma cell irradiator. In 2016 the World Health Organization encouraged field trials of transgenic male Aedes aegypti mosquitoes developed by Oxitec to try to halt the spread of the Zika virus.

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Bharat Biotech

17°39′55″N 78°36′17″E / 17.6652°N 78.6047°E / 17.6652; 78.6047 ROTAVAC, TypbarTCV, Biopolio Comvac JENVAC COVAXIN Bharat Biotech International Limited (BBIL) is an Indian multinational biotechnology company based in Hyderabad , which is engaged in drug discovery , drug development , and the manufacture of vaccines , biotherapeutics , pharmaceuticals and healthcare products. Bharat Biotech has its manufacturing facility situated at Genome Valley , Hyderabad , India. As of July 2020, the company has over 700 employees and has a presence worldwide. The company has been responsible for developing an eco-friendly recombinant and a naturally attenuated strain derived Rotavirus vaccine called ROTAVAC. They were one of the first to develop vaccines for viral diseases like Chikungunya and Zika . The company also produces vaccines for Japanese Encephalitis . Bharat Biotech has biosafety level 3 (BSL3) laboratories. In April 2020, the company announced that they have partnered with US-based company FluGen and University of Wisconsin-Madison to develop a COVID-19 vaccine. In May 2020, Indian Council of Medical Research's ( ICMR 's) National Institute of Virology approved and provided the virus strains for developing a fully indigenous COVID-19 vaccine. On June 29, 2020, the company got permission to conduct Phase 1 and Phase 2 clinical trials in India for a developmental COVID-19 vaccine named Covaxin , from the Drugs Controller General of India ( DCGI ), Government of India . The Central Drugs Laboratory (CDL) at Kasauli in Himachal Pradesh has been engaged in testing experimental batches of Bharat Biotech's COVID-19 vaccine Covaxin on a priority basis. A total of 12 sites were selected by the Indian Council for Medical Research for Phase I and II randomised, double-blind and placebo-controlled clinical trials of vaccine candidate. In September 2020, the company announced that it was going to manufacture the novel chimp-adenovirus , a single dose intranasal vaccine (codenamed BBV154 ) for COVID-19 being developed in collaboration with the American company Precision virologics and Washington University School of Medicine in St. Louis, Missouri . It is currently undergoing clinical trials. On October 12 2021, Bharat Biotech's Covaxin got approved for usage on children between 2 and 18 years of age. In March 2021, Reuters reported that Chinese state-backed cyber-espionage group Red Apollo targeted Bharat Biotech's intellectual property for exfiltration . In March 2021, Reuters reported that Chinese state-backed cyber-espionage group Red Apollo targeted Bharat Biotech's intellectual property for exfiltration .

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Tetanus vaccine

none Tetanus vaccine , also known as tetanus toxoid ( TT ), is a toxoid vaccine used to prevent tetanus . During childhood, five doses are recommended, with a sixth given during adolescence. After three doses, almost everyone is initially immune, but additional doses every ten years are recommended to maintain immunity. A booster shot should be given within 48 hours of an injury to people whose immunization is out of date. Confirming that pregnant women are up to date on tetanus immunization during each pregnancy can prevent both maternal and neonatal tetanus . The vaccine is very safe, including during pregnancy and in those with HIV/AIDS . Redness and pain at the site of injection occur in between 25% and 85% of people. Fever, feeling tired, and minor muscle pain occurs in less than 10% of people. Severe allergic reactions occur in fewer than one in 100,000 people. A number of vaccine combinations include the tetanus vaccine, such as DTaP and Tdap , which contain diphtheria , tetanus, and pertussis vaccines , and DT and Td, which contain diphtheria and tetanus vaccines. DTaP and DT are given to children less than seven years old, while Tdap and Td are given to those seven years old and older. The lowercase d and p denote lower strengths of diphtheria and pertussis vaccines. Tetanus antiserum was developed in 1890, with its protective effects lasting a few weeks. The tetanus toxoid vaccine was developed in 1924, and came into common use for soldiers in World War II . Its use resulted in a 95% decrease in the rate of tetanus. It is on the World Health Organization's List of Essential Medicines . Vaccination confers near-complete protection from tetanus, provided the individual has received their recommended booster shots. Globally, deaths from tetanus in newborns decreased from 787,000 in 1988 to 58,000 in 2010, and 34,000 deaths in 2015 (a 96% decrease from 1988). In the 1940s, before the vaccine, there were about 550 cases of tetanus per year in the United States, which has decreased to about 30 cases per year in the 2000s. Nearly all cases are among those who have never received a vaccine, or adults who have not stayed up to date on their 10-year booster shots. Guidelines on prenatal care in the United States specify that women should receive a dose of the Tdap vaccine during each pregnancy, preferably between weeks 27 and 36, to allow antibody transfer to the fetus. All postpartum women who have not previously received the Tdap vaccine are recommended to get it prior to discharge after delivery. It is recommended for pregnant women who have never received the tetanus vaccine (i.e., neither DTP or DTaP, nor DT as a child or Td or TT as an adult) to receive a series of three Td vaccinations starting during pregnancy to ensure protection against maternal and neonatal tetanus . In such cases, Tdap is recommended to be substituted for one dose of Td, again preferably between 27 and 36 weeks of gestation, and then the series completed with Td. The first vaccine is given in infancy. The baby is injected with the DTaP vaccine, which is three inactive toxins in one injection. DTaP protects against diphtheria , pertussis , and tetanus. This acellular vaccine is safer than the previously used DTP with whole inactivated pertussis (now retroactively notated DTwP ). Another option is DT, which is a combination of diphtheria and tetanus vaccines. This is given as an alternative to infants who have conflicts with the DTaP vaccine. Quadrivalent, pentavalent, and hexavalent formulations contain DTaP with one or more of the additional vaccines: inactivated polio virus vaccine (IPV), Haemophilus influenzae type b conjugate, Hepatitis B , with the availability varying in different countries. For the every ten-year booster Td or Tdap may be used, though Tdap is more expensive. Because DTaP and DT are administered to children less than a year old, the recommended location for injection is the anterolateral thigh muscle. [ medical citation needed ] However, these vaccines can be injected into the deltoid muscle if necessary. [ medical citation needed ] The World Health Organization (WHO) recommends six doses in childhood starting at six weeks of age. Four doses of DTaP are to be given in early childhood. The first dose should be around two months of age, the second at four months, the third at six, and the fourth from fifteen to eighteen months of age. There is a recommended fifth dose to be administered to four- to six-year-olds. Td and Tdap are for older children, adolescents, and adults and can be injected into the deltoid muscle. These are boosters and are recommended every ten years. It is safe to have shorter intervals between a single dose of Tdap and a dose of the Td booster. Booster shots are important because lymphocyte production (antibodies) is not at a constant high rate of activity. This is because after the introduction of the vaccine when lymphocyte production is high, the production activity of white blood cells will start to decline. The decline in activity of the T-helper cells means that there must be a booster to help keep the white blood cells active. Td and Tdap are the booster shots given every ten years to maintain immunity for adults nineteen years of age to sixty-five years of age. Tdap is given as a one-time, first-time-only dose that includes the tetanus, diphtheria, and acellular pertussis vaccinations. This should not be administered to those who are under the age of eleven or over the age of sixty-five. [ medical citation needed ] Td is the booster shot given to people over the age of seven and includes the tetanus and diphtheria toxoids . However, Td has less of the diphtheria toxoid, which is why the "d" is lowercase and the "T" is capitalized. In 2020, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommended that either tetanus and diphtheria toxoids (Td) vaccine or Tdap to be used for the decennial Td booster, tetanus prevention during wound management, and for additional required doses in the catch-up immunization schedule if a person has received at least one Tdap dose. Vaccination confers near-complete protection from tetanus, provided the individual has received their recommended booster shots. Globally, deaths from tetanus in newborns decreased from 787,000 in 1988 to 58,000 in 2010, and 34,000 deaths in 2015 (a 96% decrease from 1988). In the 1940s, before the vaccine, there were about 550 cases of tetanus per year in the United States, which has decreased to about 30 cases per year in the 2000s. Nearly all cases are among those who have never received a vaccine, or adults who have not stayed up to date on their 10-year booster shots. Guidelines on prenatal care in the United States specify that women should receive a dose of the Tdap vaccine during each pregnancy, preferably between weeks 27 and 36, to allow antibody transfer to the fetus. All postpartum women who have not previously received the Tdap vaccine are recommended to get it prior to discharge after delivery. It is recommended for pregnant women who have never received the tetanus vaccine (i.e., neither DTP or DTaP, nor DT as a child or Td or TT as an adult) to receive a series of three Td vaccinations starting during pregnancy to ensure protection against maternal and neonatal tetanus . In such cases, Tdap is recommended to be substituted for one dose of Td, again preferably between 27 and 36 weeks of gestation, and then the series completed with Td. The first vaccine is given in infancy. The baby is injected with the DTaP vaccine, which is three inactive toxins in one injection. DTaP protects against diphtheria , pertussis , and tetanus. This acellular vaccine is safer than the previously used DTP with whole inactivated pertussis (now retroactively notated DTwP ). Another option is DT, which is a combination of diphtheria and tetanus vaccines. This is given as an alternative to infants who have conflicts with the DTaP vaccine. Quadrivalent, pentavalent, and hexavalent formulations contain DTaP with one or more of the additional vaccines: inactivated polio virus vaccine (IPV), Haemophilus influenzae type b conjugate, Hepatitis B , with the availability varying in different countries. For the every ten-year booster Td or Tdap may be used, though Tdap is more expensive. Because DTaP and DT are administered to children less than a year old, the recommended location for injection is the anterolateral thigh muscle. [ medical citation needed ] However, these vaccines can be injected into the deltoid muscle if necessary. [ medical citation needed ] The World Health Organization (WHO) recommends six doses in childhood starting at six weeks of age. Four doses of DTaP are to be given in early childhood. The first dose should be around two months of age, the second at four months, the third at six, and the fourth from fifteen to eighteen months of age. There is a recommended fifth dose to be administered to four- to six-year-olds. Td and Tdap are for older children, adolescents, and adults and can be injected into the deltoid muscle. These are boosters and are recommended every ten years. It is safe to have shorter intervals between a single dose of Tdap and a dose of the Td booster. Booster shots are important because lymphocyte production (antibodies) is not at a constant high rate of activity. This is because after the introduction of the vaccine when lymphocyte production is high, the production activity of white blood cells will start to decline. The decline in activity of the T-helper cells means that there must be a booster to help keep the white blood cells active. Td and Tdap are the booster shots given every ten years to maintain immunity for adults nineteen years of age to sixty-five years of age. Tdap is given as a one-time, first-time-only dose that includes the tetanus, diphtheria, and acellular pertussis vaccinations. This should not be administered to those who are under the age of eleven or over the age of sixty-five. [ medical citation needed ] Td is the booster shot given to people over the age of seven and includes the tetanus and diphtheria toxoids . However, Td has less of the diphtheria toxoid, which is why the "d" is lowercase and the "T" is capitalized. In 2020, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommended that either tetanus and diphtheria toxoids (Td) vaccine or Tdap to be used for the decennial Td booster, tetanus prevention during wound management, and for additional required doses in the catch-up immunization schedule if a person has received at least one Tdap dose. Booster shots are important because lymphocyte production (antibodies) is not at a constant high rate of activity. This is because after the introduction of the vaccine when lymphocyte production is high, the production activity of white blood cells will start to decline. The decline in activity of the T-helper cells means that there must be a booster to help keep the white blood cells active. Td and Tdap are the booster shots given every ten years to maintain immunity for adults nineteen years of age to sixty-five years of age. Tdap is given as a one-time, first-time-only dose that includes the tetanus, diphtheria, and acellular pertussis vaccinations. This should not be administered to those who are under the age of eleven or over the age of sixty-five. [ medical citation needed ] Td is the booster shot given to people over the age of seven and includes the tetanus and diphtheria toxoids . However, Td has less of the diphtheria toxoid, which is why the "d" is lowercase and the "T" is capitalized. In 2020, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommended that either tetanus and diphtheria toxoids (Td) vaccine or Tdap to be used for the decennial Td booster, tetanus prevention during wound management, and for additional required doses in the catch-up immunization schedule if a person has received at least one Tdap dose. Common side effects of the tetanus vaccine include fever, redness, and swelling with soreness or tenderness around the injection site (one in five people have redness or swelling). Body aches and tiredness have been reported following Tdap. Td / Tdap can cause painful swelling of the entire arm in one of 500 people. Tetanus toxoid containing vaccines (DTaP, DTP, Tdap, Td, DT) may cause brachial neuritis at a rate of one out of every 100,000 to 200,000 doses. The type of vaccination for this disease is called artificial active immunity . This type of immunity is generated when a dead or weakened version of the disease enters the body, causing an immune response which includes the production of antibodies . This is beneficial because it means that if the disease is ever introduced into the body, the immune system will recognize the antigen and produce antibodies more rapidly. The first vaccine for passive immunology was discovered by a group of German scientists under the leadership of Emil von Behring in 1890. The first inactive tetanus toxoid was discovered and produced in 1924. A more effective adsorbed version of the vaccine, created in 1938, was proven to be successful when it was used to prevent tetanus in the military during World War II . DTP/DTwP (which is the combined vaccine for diphtheria , tetanus, and pertussis ) was first used in 1948, and was continued until 1991, when it was replaced with an acellular form of the pertussis vaccine due to safety concerns. Half of those who received the DT(w)P vaccine had redness, swelling, and pain around the injection site, which convinced researchers to find a replacement vaccine. Two new vaccines were launched in 1992. These combined tetanus and diphtheria with acellular pertussis (TDaP or DTaP), which could be given to adolescents and adults (as opposed to previously when the vaccine was only given to children).

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Wart

Warts are non-cancerous viral growths usually occurring on the hands and feet but can also affect other locations, such as the genitals or face. One or many warts may appear. They are distinguished from cancerous tumors as they are caused by a viral infection, such as a human papillomavirus , rather than a cancerous growth . Factors that increase the risk include the use of public showers and pools, working with meat, eczema , and a weak immune system . The virus is believed to infect the host through the entrance of a skin wound . A number of types exist, including plantar warts , " filiform warts ", and genital warts . Genital warts are often sexually transmitted . Without treatment, most types of warts resolve in months to years. A number of treatments may speed resolution, including salicylic acid applied to the skin and cryotherapy . In those who are otherwise healthy, they do not typically result in significant problems. Treatment of genital warts differs from that of other types. Infection of a virus, such as HIV , can cause warts. This is prevented through careful handling of needles or sharp objects that could infect the individual through physical trauma of the skin, plus the practice of safe sex , and sexual abstinence . Viruses that are not sexually transmitted, or are not transmitted in the case of a wart, can be prevented through a number of behaviors, such as wearing shoes outdoors and avoiding unsanitized areas without proper shoes or clothing, such as public restrooms or locker rooms. Warts are very common, with most people being infected at some point in their lives. The estimated current rate of non-genital warts among the general population is 1–13%. They are more common among young people. Prior to widespread adoption of the HPV vaccine , the estimated rate of genital warts in sexually active women was 12%. Warts have been described at least as far back as 400 BC by Hippocrates . A range of types of wart have been identified, varying in shape and site affected, as well as the type of human papillomavirus involved. These include:Warts are caused by the human papillomavirus (HPV). There are about 130 known types of human papillomaviruses. HPV infects the squamous epithelium , usually of the skin or genitals, but each HPV type is typically only able to infect a few specific areas of the body. Many HPV types can produce a benign growth, often called a "wart" or "papilloma", in the area they infect. Many of the more common HPV and wart types are listed below. High-risk: 16, 18 (cause the most cervical cancer); also 31, 33, 35, 39, 45, 52, 58, 59, and others. Low-risk: 6, 11 (most common); also 13, 44, 40, 43, 42, 54, 61, 72, 81, 89, and others.Common warts have a characteristic appearance under the microscope. They have thickening of the stratum corneum (hyperkeratosis), thickening of the stratum spinosum (acanthosis), thickening of the stratum granulosum , rete ridge elongation, and large blood vessels at the dermoepidermal junction . [ citation needed ]On dermatoscopic examination, warts will commonly have fingerlike or knoblike extensions. Gardasil 6 is an HPV vaccine aimed at preventing cervical cancers and genital warts. Gardasil is designed to prevent infection with HPV types 16, 18, 6, and 11. HPV types 16 and 18 currently cause about 70% of cervical cancer cases, and also cause some vulvar , vaginal , penile and anal cancers . HPV types 6 and 11 are responsible for 90% of documented cases of genital warts. Gardasil 9 protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. HPV vaccines do not currently protect against the virus strains responsible for plantar warts (verrucae). The virus is relatively hardy and immune to many common disinfectants . Exposure to 90% ethanol for at least 1 minute, 2% glutaraldehyde , [ citation needed ] 30% Savlon , and/or 1% sodium hypochlorite can disinfect the pathogen. The virus is resistant to drying and heat, but killed by 100 °C (212 °F) temperature and ultraviolet radiation. The virus is relatively hardy and immune to many common disinfectants . Exposure to 90% ethanol for at least 1 minute, 2% glutaraldehyde , [ citation needed ] 30% Savlon , and/or 1% sodium hypochlorite can disinfect the pathogen. The virus is resistant to drying and heat, but killed by 100 °C (212 °F) temperature and ultraviolet radiation. There are many treatments and procedures associated with wart removal. A review of various skin wart treatments concluded that topical treatments containing salicylic acid were more effective than placebo . Cryotherapy appears to be as effective as salicylic acid, but there have been fewer trials. Daily application of the latex of Chelidonium majus is a traditional treatment. The acrid yellow sap of Greater Celandine is used as a traditional wart remedy. According to English folk belief , touching toads causes warts; according to a German belief, touching a toad under a full moon cures warts. The most common Northern Hemisphere toads have glands that protrude from their skin that superficially resemble warts. Warts are caused by a virus, and toads do not harbor it. A variety of traditional folk remedies and rituals claim to be able to remove warts. In The Adventures of Tom Sawyer , Mark Twain has his characters discuss a variety of such remedies. Tom Sawyer proposes "spunk-water" (or "stump-water", the water collecting in the hollow of a tree stump) as a remedy for warts on the hand. You put your hand into the water at midnight and say: Barley-corn, barley-corn, injun-meal shorts, Spunk-water, spunk-water, swaller these warts You then "walk away quick, eleven steps, with your eyes shut, and then turn around three times and walk home without speaking to anybody. Because if you speak the charm's busted." This is given as an example of Huckleberry Finn 's planned remedy, which involves throwing a dead cat into a graveyard as a devil or devils comes to collect a recently buried wicked person. Another remedy involved splitting a bean, drawing blood from the wart and putting it on one of the halves, and burying that half at a crossroads at midnight. The theory of operation is that the blood on the buried bean will draw away the wart. Twain is recognized as an early collector and recorder of genuine American folklore . Similar practices are recorded elsewhere. In Louisiana , one remedy for warts involves rubbing the wart with a potato , which is then buried; when the "buried potato dries up, the wart will be cured". Another remedy similar to Twain's is reported from Northern Ireland , where water from a specific well on Rathlin Island is credited with the power to cure warts. Daily application of the latex of Chelidonium majus is a traditional treatment. The acrid yellow sap of Greater Celandine is used as a traditional wart remedy. According to English folk belief , touching toads causes warts; according to a German belief, touching a toad under a full moon cures warts. The most common Northern Hemisphere toads have glands that protrude from their skin that superficially resemble warts. Warts are caused by a virus, and toads do not harbor it. A variety of traditional folk remedies and rituals claim to be able to remove warts. In The Adventures of Tom Sawyer , Mark Twain has his characters discuss a variety of such remedies. Tom Sawyer proposes "spunk-water" (or "stump-water", the water collecting in the hollow of a tree stump) as a remedy for warts on the hand. You put your hand into the water at midnight and say: Barley-corn, barley-corn, injun-meal shorts, Spunk-water, spunk-water, swaller these warts You then "walk away quick, eleven steps, with your eyes shut, and then turn around three times and walk home without speaking to anybody. Because if you speak the charm's busted." This is given as an example of Huckleberry Finn 's planned remedy, which involves throwing a dead cat into a graveyard as a devil or devils comes to collect a recently buried wicked person. Another remedy involved splitting a bean, drawing blood from the wart and putting it on one of the halves, and burying that half at a crossroads at midnight. The theory of operation is that the blood on the buried bean will draw away the wart. Twain is recognized as an early collector and recorder of genuine American folklore . Similar practices are recorded elsewhere. In Louisiana , one remedy for warts involves rubbing the wart with a potato , which is then buried; when the "buried potato dries up, the wart will be cured". Another remedy similar to Twain's is reported from Northern Ireland , where water from a specific well on Rathlin Island is credited with the power to cure warts. Surviving ancient medical texts show that warts were a documented disease since at least the time of Hippocrates , who lived c. 460 – c. 370 BC . In the book De Medecia by the Roman physician Aulus Cornelius Celsus , who lived c. 25 BC – c. 50 AD , different types of warts were described. Celsus described Myrmecia , today recognized as plantar wart , and categorized acrochordon (a skin tag) as a wart. In the 13th century, warts were described in books published by the surgeons William of Saliceto and Lanfranc of Milan . The word verruca to describe a wart was introduced by the physician Daniel Sennert , who described warts in his 1636 book Hypomnemata physicae . The cause of warts was initially disputed in the medical profession. In the early 18th century the physician Daniel Turner , who published the first book on dermatology , suggested that warts were caused by damaged nerves close to the skin. In the mid-18th century, the surgeon John Hunter popularized the belief that warts were caused by a bacterial syphilis infection. The surgeon Benjamin Bell documented that warts were caused by a disease entirely unrelated to syphilis, and established a causal link between warts and cancer. In the 19th century, the chief physician of Verona Hospital established a link between warts and cervical cancer . But in 1874 it was noted by the dermatologist Ferdinand Ritter von Hebra that while various theories were advanced by the medical profession, the "influences causing warts are still very obscure". In 1907 the physician Giuseppe Ciuffo was the first to demonstrate that warts were caused by a virus infection. In 1976 the virologist Harald zur Hausen was the first to discover that warts were caused by the human papillomavirus (HPV). His continuous research established the evidence necessary to develop a HPV vaccine , which first became available in 2006.

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BCG vaccine

none Bacillus Calmette–Guérin ( BCG ) vaccine is a vaccine primarily used against tuberculosis (TB). It is named after its inventors Albert Calmette and Camille Guérin . In countries where tuberculosis or leprosy is common, one dose is recommended in healthy babies as soon after birth as possible. In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated. Adults who do not have tuberculosis and have not been previously immunized, but are frequently exposed, may be immunized, as well. BCG also has some effectiveness against Buruli ulcer infection and other nontuberculous mycobacterial infections. Additionally, it is sometimes used as part of the treatment of bladder cancer . Rates of protection against tuberculosis infection vary widely and protection lasts up to 20 years. Among children, it prevents about 20% from getting infected and among those who do get infected, it protects half from developing disease. The vaccine is given by injection into the skin. No evidence shows that additional doses are beneficial. Serious side effects are rare. Often, redness, swelling, and mild pain occur at the site of injection. A small ulcer may also form with some scarring after healing. Side effects are more common and potentially more severe in those with immunosuppression . Although no harmful effects on the fetus have been observed, there is insufficient evidence about the safety of BCG vaccination during pregnancy and therefore the vaccine is not recommended for use during pregnancy. The vaccine was originally developed from Mycobacterium bovis , which is commonly found in cattle. While it has been weakened, it is still live . The BCG vaccine was first used medically in 1921. It is on the World Health Organization's List of Essential Medicines . As of 2004 [ update ] , the vaccine is given to about 100 million children per year globally. The main use of BCG is for vaccination against tuberculosis . BCG vaccine can be administered after birth intradermally. BCG vaccination can cause a false positive Mantoux test . The most controversial aspect of BCG is the variable efficacy found in different clinical trials, which appears to depend on geography. Trials conducted in the UK have consistently shown a protective effect of 60 to 80%, but those conducted elsewhere have shown no protective effect, and efficacy appears to fall the closer one gets to the equator. A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%. Differences in effectiveness depend on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the laboratory where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium. A systematic review and meta-analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active tuberculosis by 71%. The studies included in this review were limited to those that used interferon gamma release assay . The duration of protection of BCG is not clearly known. In those studies showing a protective effect, the data are inconsistent. The MRC study showed protection waned to 59% after 15 years and to zero after 20 years; however, a study looking at Native Americans immunized in the 1930s found evidence of protection even 60 years after immunization, with only a slight waning in efficacy. BCG seems to have its greatest effect in preventing miliary tuberculosis or tuberculosis meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible. The 100th anniversary of BCG was in 2021. It remains the only vaccine licensed against tuberculosis, which is an ongoing pandemic . Tuberculosis elimination is a goal of the World Health Organization (WHO), although the development of new vaccines with greater efficacy against adult pulmonary tuberculosis may be needed to make substantial progress. A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None has been proven, some have been disproved, and none can explain the lack of efficacy in both low tuberculosis-burden countries (US) and high tuberculosis-burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG. BCG has protective effects against some nontuberculosis mycobacteria. BCG has been one of the most successful immunotherapies. BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977. By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of nonmuscle-invasive bladder cancer. The main use of BCG is for vaccination against tuberculosis . BCG vaccine can be administered after birth intradermally. BCG vaccination can cause a false positive Mantoux test . The most controversial aspect of BCG is the variable efficacy found in different clinical trials, which appears to depend on geography. Trials conducted in the UK have consistently shown a protective effect of 60 to 80%, but those conducted elsewhere have shown no protective effect, and efficacy appears to fall the closer one gets to the equator. A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%. Differences in effectiveness depend on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the laboratory where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium. A systematic review and meta-analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active tuberculosis by 71%. The studies included in this review were limited to those that used interferon gamma release assay . The duration of protection of BCG is not clearly known. In those studies showing a protective effect, the data are inconsistent. The MRC study showed protection waned to 59% after 15 years and to zero after 20 years; however, a study looking at Native Americans immunized in the 1930s found evidence of protection even 60 years after immunization, with only a slight waning in efficacy. BCG seems to have its greatest effect in preventing miliary tuberculosis or tuberculosis meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible. The 100th anniversary of BCG was in 2021. It remains the only vaccine licensed against tuberculosis, which is an ongoing pandemic . Tuberculosis elimination is a goal of the World Health Organization (WHO), although the development of new vaccines with greater efficacy against adult pulmonary tuberculosis may be needed to make substantial progress. A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None has been proven, some have been disproved, and none can explain the lack of efficacy in both low tuberculosis-burden countries (US) and high tuberculosis-burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG. A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None has been proven, some have been disproved, and none can explain the lack of efficacy in both low tuberculosis-burden countries (US) and high tuberculosis-burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG. BCG has protective effects against some nontuberculosis mycobacteria. BCG has been one of the most successful immunotherapies. BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977. By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of nonmuscle-invasive bladder cancer. A pre-injection tuberculin skin test is usually carried out before administering BCG. A reactive tuberculin skin test is a contraindication to BCG due to the risk of severe local inflammation and scarring; it does not indicate any immunity. BCG is also contraindicated in certain people who have IL-12 receptor pathway defects. [ citation needed ] BCG is given as a single intradermal injection at the insertion of the deltoid . If BCG is accidentally given subcutaneously , then a local abscess may form (a "BCG-oma") that can sometimes ulcerate, and may require treatment with antibiotics immediately, otherwise without treatment it could spread the infection, causing severe damage to vital organs. An abscess is not always associated with incorrect administration, and it is one of the more common complications that can occur with the vaccination. Numerous medical studies on treatment of these abscesses with antibiotics have been done with varying results, but the consensus is once pus is aspirated and analysed, provided no unusual bacilli are present, the abscess will generally heal on its own in a matter of weeks. The characteristic raised scar that BCG immunization leaves is often used as proof of prior immunization. This scar must be distinguished from that of smallpox vaccination , which it may resemble. [ citation needed ] When given for bladder cancer, the vaccine is not injected through the skin, but is instilled into the bladder through the urethra using a soft catheter. BCG immunization generally causes some pain and scarring at the site of injection. The main adverse effects are keloids —large, raised scars. The insertion to the deltoid muscle is most frequently used because the local complication rate is smallest when that site is used. Nonetheless, the buttock is an alternative site of administration because it provides better cosmetic outcomes. [ citation needed ] BCG vaccine should be given intradermally. If given subcutaneously, it may induce local infection and spread to the regional lymph nodes , causing either suppurative (production of pus ) and nonsuppurative lymphadenitis . Conservative management is usually adequate for nonsuppurative lymphadenitis. If suppuration occurs, it may need needle aspiration . For nonresolving suppuration, surgical excision may be required. Evidence for the treatment of these complications is scarce. Uncommonly, breast and gluteal abscesses can occur due to haematogenous (carried by the blood) and lymphangiomatous spread. Regional bone infection (BCG osteomyelitis or osteitis ) and disseminated BCG infection are rare complications of BCG vaccination, but potentially life-threatening. Systemic antituberculous therapy may be helpful in severe complications. When BCG is used for bladder cancer, around 2.9% of treated patients discontinue immunotherapy due to a genitourinary or systemic BCG-related infection, however while symptomatic bladder BCG infection is frequent, the involvement of other organs is very uncommon. When systemic involvement occurs, liver and lungs are the first organs to be affected (1 week [median] after the last BCG instillation). If BCG is accidentally given to an immunocompromised patient (e.g., an infant with severe combined immune deficiency ), it can cause disseminated or life-threatening infection. The documented incidence of this happening is less than one per million immunizations given. In 2007, the WHO stopped recommending BCG for infants with HIV , even if the risk of exposure to tuberculosis is high, because of the risk of disseminated BCG infection (which is roughly 400 per 100,000 in that higher risk context). The age of the person and the frequency with which BCG is given has always varied from country to country. The WHO currently recommends childhood BCG for all countries with a high incidence of tuberculosis and/or high leprosy burden. This is a partial list of historic and current BCG practice around the globe. A complete atlas of past and present practice has been generated. BCG is prepared from a strain of the attenuated ( virulence -reduced) live bovine tuberculosis bacillus, Mycobacterium bovis , that has lost its ability to cause disease in humans. It is specially subcultured in a culture medium, usually Middlebrook 7H9 . Because the living bacilli evolve to make the best use of available nutrients, they become less well-adapted to human blood and can no longer induce disease when introduced into a human host. Still, they are similar enough to their wild ancestors to provide some degree of immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for a duration of 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown. A number of different companies make BCG, sometimes using different genetic strains of the bacterium. This may result in different product characteristics. OncoTICE, used for bladder instillation for bladder cancer, was developed by Organon Laboratories (since acquired by Schering-Plough , and in turn acquired by Merck & Co. ). A similar application is the product of Onko BCG of the Polish company Biomed-Lublin , which owns the Brazilian substrain M. bovis BCG Moreau which is less reactogenic than vaccines including other BCG strains. Pacis BCG, made from the Montréal (Institut Armand-Frappier) strain, was first marketed by Urocor in about 2002. Urocor was since acquired by Dianon Systems. Evans Vaccines (a subsidiary of PowderJect Pharmaceuticals ). Statens Serum Institut in Denmark markets BCG vaccine prepared using Danish strain 1331. Japan BCG Laboratory markets its vaccine, based on the Tokyo 172 substrain of Pasteur BCG, in 50 countries worldwide. According to a UNICEF report published in December 2015, on BCG vaccine supply security, global demand increased in 2015 from 123 to 152.2 million doses. To improve security and to [diversify] sources of affordable and flexible supply," UNICEF awarded seven new manufacturers contracts to produce BCG. Along with supply availability from existing manufacturers, and a "new WHO prequalified vaccine" the total supply will be "sufficient to meet both suppressed 2015 demand carried over to 2016, as well as total forecast demand through 2016–2018." In 2011, the Sanofi Pasteur plant flooded, causing problems with mold. The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products made with substrain Connaught such as a tuberculosis vaccine and ImmuCYST, a BCG immunotherapeutic and bladder cancer drug. By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits. The resulting closure of the plant for over two years caused shortages of bladder cancer and tuberculosis vaccines. On 29 October 2014 Health Canada gave the permission for Sanofi to resume production of BCG. A 2018 analysis of the global supply concluded that the supplies are adequate to meet forecast BCG vaccine demand, but that risks of shortages remain, mainly due to dependence of 75 percent of WHO pre-qualified supply on just two suppliers. Some BCG vaccines are freeze dried and become fine powder. Sometimes the powder is sealed with vacuum in a glass ampoule. Such a glass ampoule has to be opened slowly to prevent the airflow from blowing out the powder. Then the powder has to be diluted with saline water before injecting. In 2011, the Sanofi Pasteur plant flooded, causing problems with mold. The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products made with substrain Connaught such as a tuberculosis vaccine and ImmuCYST, a BCG immunotherapeutic and bladder cancer drug. By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits. The resulting closure of the plant for over two years caused shortages of bladder cancer and tuberculosis vaccines. On 29 October 2014 Health Canada gave the permission for Sanofi to resume production of BCG. A 2018 analysis of the global supply concluded that the supplies are adequate to meet forecast BCG vaccine demand, but that risks of shortages remain, mainly due to dependence of 75 percent of WHO pre-qualified supply on just two suppliers. Some BCG vaccines are freeze dried and become fine powder. Sometimes the powder is sealed with vacuum in a glass ampoule. Such a glass ampoule has to be opened slowly to prevent the airflow from blowing out the powder. Then the powder has to be diluted with saline water before injecting. The history of BCG is tied to that of smallpox . By 1865 Jean Antoine Villemin had demonstrated that rabbits could be infected with tuberculosis from humans; by 1868 he had found that rabbits could be infected with tuberculosis from cows, and that rabbits could be infected with tuberculosis from other rabbits. Thus, he concluded that tuberculosis was transmitted via some unidentified microorganism (or "virus" , as he called it). In 1882 Robert Koch regarded human and bovine tuberculosis as identical. But in 1895, Theobald Smith presented differences between human and bovine tuberculosis, which he reported to Koch. By 1901 Koch distinguished Mycobacterium bovis from Mycobacterium tuberculosis . Following the success of vaccination in preventing smallpox, established during the 18th century, scientists thought to find a corollary in tuberculosis by drawing a parallel between bovine tuberculosis and cowpox : it was hypothesized that infection with bovine tuberculosis might protect against infection with human tuberculosis. In the late 19th century, clinical trials using M. bovis were conducted in Italy with disastrous results, because M. bovis was found to be just as virulent as M. tuberculosis . [ citation needed ] Albert Calmette , a French physician and bacteriologist, and his assistant and later colleague, Camille Guérin , a veterinarian, were working at the Institut Pasteur de Lille ( Lille , France) in 1908. Their work included subculturing virulent strains of the tuberculosis bacillus and testing different culture media. They noted a glycerin-bile-potato mixture grew bacilli that seemed less virulent, and changed the course of their research to see if repeated subculturing would produce a strain that was attenuated enough to be considered for use as a vaccine. The BCG strain was isolated after subculturing 239 times during 13 years from virulent strain on glycerine potato medium. The research continued throughout World War I until 1919, when the now avirulent bacilli were unable to cause tuberculosis disease in research animals. Calmette and Guerin transferred to the Paris Pasteur Institute in 1919. The BCG vaccine was first used in humans in 1921. Public acceptance was slow, and the Lübeck disaster , in particular, did much to harm it. Between 1929 and 1933 in Lübeck , 251 infants were vaccinated in the first 10 days of life; 173 developed tuberculosis and 72 died. It was subsequently discovered that the BCG administered there had been contaminated with a virulent strain that was being stored in the same incubator, which led to legal action against the manufacturers of the vaccine. Dr. R. G. Ferguson , working at the Fort Qu'Appelle Sanatorium in Saskatchewan, was among the pioneers in developing the practice of vaccination against tuberculosis. In Canada, more than 600 children from residential schools were used as involuntary participants in BCG vaccine trials between 1933 and 1945. In 1928, BCG was adopted by the Health Committee of the League of Nations (predecessor to the World Health Organization (WHO)). Because of opposition, however, it only became widely used after World War II. From 1945 to 1948, relief organizations (International Tuberculosis Campaign or Joint Enterprises) vaccinated over eight million babies in eastern Europe and prevented the predicted typical increase of tuberculosis after a major war. [ citation needed ] BCG is very efficacious against tuberculous meningitis in the pediatric age group, but its efficacy against pulmonary tuberculosis appears to be variable. Some countries have removed BCG from routine vaccination. Two countries that have never used it routinely are the United States and the Netherlands (in both countries, it is felt that having a reliable Mantoux test and therefore being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is now relatively rare there). Other names include "Vaccin Bilié de Calmette et Guérin vaccine" and "Bacille de Calmette et Guérin vaccine". [ citation needed ]Tentative evidence exists for a beneficial non-specific effect of BCG vaccination on overall mortality in low income countries, or for its reducing other health problems including sepsis and respiratory infections when given early, with greater benefit the earlier it is used. In rhesus macaques , BCG shows improved rates of protection when given intravenously . Some risks must be evaluated before it can be translated to humans. The University of Oxford Jenner Institute is conducting a study comparing the efficacy of injected versus inhaled BCG vaccine in already-vaccinated adults. As of 2017 [ update ] , BCG vaccine is in the early stages of being studied in type 1 diabetes (T1D). Use of the BCG vaccine may provide protection against COVID-19. However, epidemiologic observations in this respect are ambiguous. The WHO does not recommend its use for prevention as of 12 January 2021 [ update ] . As of January 2021 [ update ] , twenty BCG trials are in various clinical stages. As of October 2022 [ update ] , the results are extremely mixed. A 15-month trial involving people thrice-vaccinated over the two years before the pandemic shows positive results in preventing infection in BCG-naive people with type 1 diabetes. On the other hand, a 5-month trial shows that re-vaccinating with BCG does not help prevent infection in healthcare workers. Both of these trials were double-blind randomized controlled trials . As of 2017 [ update ] , BCG vaccine is in the early stages of being studied in type 1 diabetes (T1D). Use of the BCG vaccine may provide protection against COVID-19. However, epidemiologic observations in this respect are ambiguous. The WHO does not recommend its use for prevention as of 12 January 2021 [ update ] . As of January 2021 [ update ] , twenty BCG trials are in various clinical stages. As of October 2022 [ update ] , the results are extremely mixed. A 15-month trial involving people thrice-vaccinated over the two years before the pandemic shows positive results in preventing infection in BCG-naive people with type 1 diabetes. On the other hand, a 5-month trial shows that re-vaccinating with BCG does not help prevent infection in healthcare workers. Both of these trials were double-blind randomized controlled trials .

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Moderna

42°21′48″N 71°05′28″W / 42.3633°N 71.091°W / 42.3633; -71.091 Moderna, Inc. ( / m ə ˈ d ɜːr n ə / mə- DUR -nə ) is a pharmaceutical and biotechnology company based in Cambridge, Massachusetts , that focuses on RNA therapeutics , primarily mRNA vaccines . These vaccines use a copy of a molecule called messenger RNA (mRNA) to carry instructions for proteins to produce an immune response . The company's name is derived from the terms "modified", "RNA", and "modern". The company's only commercial product is the Moderna COVID-19 vaccine , marketed as Spikevax. The company has 45 treatment and vaccine candidates, of which 38 have entered clinical trials . Candidates include possible vaccines for influenza , HIV , respiratory syncytial virus , Epstein–Barr virus , the Nipah virus , chikungunya , human metapneumovirus , varicella zoster virus , as well as a cytomegalovirus vaccine , a Zika virus vaccine funded by the Biomedical Advanced Research and Development Authority , and three cancer vaccines . The company's pipeline also includes a cell therapy -based treatment: a relaxin fusion protein being developed to treat acute decompensated heart failure . It also includes candidates that use OX40 ligand , interleukin 23 , IL36G , and interleukin 12 for cancer immunotherapy , specifically treatment of breast cancer , urothelial carcinoma , lymphoma , and melanoma . Also being developed by Moderna is a regenerative medicine treatment that encodes vascular endothelial growth factor A to stimulate blood vessel growth for patients with myocardial ischemia . Moderna was founded in 2010 by Derrick Rossi , Timothy A. Springer , Kenneth R. Chien , Robert S. Langer , and Noubar Afeyan . Stéphane Bancel , the current CEO, was appointed as CEO in 2011. Between 2011 and 2017, Moderna raised $2 billion in venture capital funding. In 2013, the company formed a partnership with AstraZeneca to develop treatments for cardiovascular, metabolic, and renal diseases, as well as cancer. Moderna also was awarded a $25,000,000 grant by DARPA through a program Autonomous Diagnostics to Enable Prevention and Therapeutics: Prophylactic Options to Environmental and Contagious Threats (ADEPT-PROTECT). Its stated goal was to develop an mRNA vaccine with the capability to suppress a global pandemic within 60 days. In January 2014, the company entered an agreement with Alexion Pharmaceuticals to develop treatments against ten diseases. On January 14, 2014, Moderna announced the creation of its first venture, Onkaido Therapeutics, to focus "exclusively on developing mRNA-based oncology treatments." It launched its second venture, Valera, in January 2015, with a focus on "viral, bacterial and parasitic infectious diseases." Employees of Valera and Moderna developed an mRNA vaccine candidate against Zika virus infection. Another venture, Elpidera, was announced in May 2015 to continue work on RNA therapies advancing Moderna's work with Alexion. In 2015, the company formed a partnership with Merck & Co. to develop treatments for cancer, and in 2016 the company formed a partnership with Vertex Pharmaceuticals to develop treatments for cystic fibrosis . In January 2016, the Bill & Melinda Gates Foundation committed to provide at least $20 million in grant funding to the company. In 2017, Alexion terminated its partnership with Moderna after safety issues prevented their work from reaching human trials. In July 2018, the company opened a 200,000 square foot facility in Norwood, Massachusetts for manufacturing, preclinical and clinical work. In December 2018, Moderna became a public company via the largest initial public offering of a biotechnology company in history, raising $621 million by selling 27 million shares at $23 per share. The first mRNA vaccine developed by Moderna was for influenza in 2015, and its first antibody encoded by mRNA was in 2019. In 2023, Moderna acquired OriCiro Genomics, a Japanese manufacturer of genetic engineering tools, in its first acquisition. In early 2023, the company in collaboration with Merck won breakthrough status from the FDA for its mRNA-4157/V940 drug candidate, a cancer vaccine . In July 2023, the company entered into an agreement with the Chinese government to develop mRNA drugs for exclusive use in China . From 2020 to 2021, Moderna received $955 million from Operation Warp Speed to accelerate development of its COVID-19 vaccine, with $4.9 billion committed in total for producing 300 million vaccine doses. In March 2020, the Food and Drug Administration approved clinical trials for the Moderna COVID‑19 vaccine candidate, and in December, the vaccine, mRNA-1273, was issued an emergency use authorization in the United States. In 2022, it gained FDA approval both for the monovalent vaccine , Spikevax , and a bivalent booster . In April 2022, Moderna announced plans to build a $180 million vaccine factory in Montreal , forming a 10-year partnership with the Government of Canada , Quebec , and McGill University to produce 100 million Spikevax doses annually and expand vaccine research capabilities. The plant is scheduled to supply COVID-19 vaccines in the fall of 2025. In February 2023, the company agreed to pay $400 million to the National Institutes of Health , Dartmouth College , and Scripps Research to settle a dispute over the rights to a chemical technique that was used in the vaccine. In April 2023, a court affirmed a decision to cancel a patent by Arbutus Biopharma after a patent dispute with Moderna regarding its COVID-19 vaccine. Several legal cases between Moderna and Pfizer and BioNTech in various countries, alleging that the Pfizer–BioNTech COVID-19 vaccine violates the patent on Moderna's mRNA vaccine technology, are ongoing. In 2013, the company formed a partnership with AstraZeneca to develop treatments for cardiovascular, metabolic, and renal diseases, as well as cancer. Moderna also was awarded a $25,000,000 grant by DARPA through a program Autonomous Diagnostics to Enable Prevention and Therapeutics: Prophylactic Options to Environmental and Contagious Threats (ADEPT-PROTECT). Its stated goal was to develop an mRNA vaccine with the capability to suppress a global pandemic within 60 days. In January 2014, the company entered an agreement with Alexion Pharmaceuticals to develop treatments against ten diseases. On January 14, 2014, Moderna announced the creation of its first venture, Onkaido Therapeutics, to focus "exclusively on developing mRNA-based oncology treatments." It launched its second venture, Valera, in January 2015, with a focus on "viral, bacterial and parasitic infectious diseases." Employees of Valera and Moderna developed an mRNA vaccine candidate against Zika virus infection. Another venture, Elpidera, was announced in May 2015 to continue work on RNA therapies advancing Moderna's work with Alexion. In 2015, the company formed a partnership with Merck & Co. to develop treatments for cancer, and in 2016 the company formed a partnership with Vertex Pharmaceuticals to develop treatments for cystic fibrosis . In January 2016, the Bill & Melinda Gates Foundation committed to provide at least $20 million in grant funding to the company. In 2017, Alexion terminated its partnership with Moderna after safety issues prevented their work from reaching human trials. In July 2018, the company opened a 200,000 square foot facility in Norwood, Massachusetts for manufacturing, preclinical and clinical work. In December 2018, Moderna became a public company via the largest initial public offering of a biotechnology company in history, raising $621 million by selling 27 million shares at $23 per share. The first mRNA vaccine developed by Moderna was for influenza in 2015, and its first antibody encoded by mRNA was in 2019. In 2023, Moderna acquired OriCiro Genomics, a Japanese manufacturer of genetic engineering tools, in its first acquisition. In early 2023, the company in collaboration with Merck won breakthrough status from the FDA for its mRNA-4157/V940 drug candidate, a cancer vaccine . In July 2023, the company entered into an agreement with the Chinese government to develop mRNA drugs for exclusive use in China . From 2020 to 2021, Moderna received $955 million from Operation Warp Speed to accelerate development of its COVID-19 vaccine, with $4.9 billion committed in total for producing 300 million vaccine doses. In March 2020, the Food and Drug Administration approved clinical trials for the Moderna COVID‑19 vaccine candidate, and in December, the vaccine, mRNA-1273, was issued an emergency use authorization in the United States. In 2022, it gained FDA approval both for the monovalent vaccine , Spikevax , and a bivalent booster . In April 2022, Moderna announced plans to build a $180 million vaccine factory in Montreal , forming a 10-year partnership with the Government of Canada , Quebec , and McGill University to produce 100 million Spikevax doses annually and expand vaccine research capabilities. The plant is scheduled to supply COVID-19 vaccines in the fall of 2025. In February 2023, the company agreed to pay $400 million to the National Institutes of Health , Dartmouth College , and Scripps Research to settle a dispute over the rights to a chemical technique that was used in the vaccine. In April 2023, a court affirmed a decision to cancel a patent by Arbutus Biopharma after a patent dispute with Moderna regarding its COVID-19 vaccine. Several legal cases between Moderna and Pfizer and BioNTech in various countries, alleging that the Pfizer–BioNTech COVID-19 vaccine violates the patent on Moderna's mRNA vaccine technology, are ongoing.

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Viral hemorrhagic fever

Viral hemorrhagic fevers ( VHFs ) are a diverse group of animal and human illnesses . VHFs may be caused by five distinct families of RNA viruses : the families Filoviridae , Flaviviridae , Rhabdoviridae , and several member families of the Bunyavirales order such as Arenaviridae , and Hantaviridae . All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in many cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica (a hantavirus ), while others, such as Ebola virus , can cause severe, life-threatening disease.Signs and symptoms of VHFs include (by definition) fever and bleeding: The severity of symptoms varies with the type of virus. The "VHF syndrome" (capillary leak, bleeding diathesis , and circulatory compromise leading to shock) appears in a majority of people with filoviral hemorrhagic fevers (e.g., Ebola and Marburg virus ), Crimean–Congo hemorrhagic fever (CCHF), and the South American hemorrhagic fevers caused by arenaviruses , but only in a small minority of patients with dengue or Rift Valley fever .Five families of RNA viruses have been recognised as being able to cause hemorrhagic fevers. [ citation needed ] The pathogen that caused the cocoliztli epidemics in Mexico of 1545 and 1576 is still unknown, and the 1545 epidemic may have been bacterial rather than viral. Different hemorrhagic fever viruses act on the body in different ways, resulting in different symptoms. In most VHFs, it is likely that several mechanisms contribute to symptoms, including liver damage, disseminated intravascular coagulation (DIC), and bone marrow dysfunction. In DIC, small blood clots form in blood vessels throughout the body, removing platelets necessary for clotting from the bloodstream and reducing clotting ability. DIC is thought to cause bleeding in Rift Valley, Marburg, and Ebola fevers. For filoviral hemorrhagic fevers, there are four general mechanisms of pathogenesis. The first mechanism is dissemination of virus due to suppressed responses by macrophages and dendritic cell (antigen presenting cells). The second mechanism is prevention of antigen specific immune response. The third mechanism is apoptosis of lymphocytes. The fourth mechanism is when infected macrophages interact with toxic cytokines , leading to diapedesis and coagulation deficiency. From the vascular perspective, the virus will infect vascular endothelial cells, leading to the reorganization of the VE-cadherin catenin complex (a protein important in cell adhesion). This reorganization creates intercellular gaps in endothelial cells. The gaps lead to increased endothelial permeability and allow blood to escape from the vascular circulatory system. [ citation needed ] The reasons for variation among patients infected with the same virus are unknown but stem from a complex system of virus-host interactions. Dengue fever becomes more virulent during a second infection by means of antibody-dependent enhancement . After the first infection, macrophages display antibodies on their cell membranes specific to the dengue virus. By attaching to these antibodies, dengue viruses from a second infection are better able to infect the macrophages, thus reducing the immune system's ability to fight off infection. [ citation needed ]Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment capabilities. The findings of laboratory investigation vary somewhat between the viruses but in general, there is a decrease in the total white cell count (particularly the lymphocytes ), a decrease in the platelet count, an increase in the blood serum liver enzymes , and reduced blood clotting ability measured as an increase in both the prothrombin (PT) and activated partial thromboplastin times (PTT). The hematocrit may be elevated. The serum urea and creatine may be raised but this is dependent on the hydration status of the patient. The bleeding time tends to be prolonged. [ citation needed ]With the exception of yellow fever vaccine and Ebola vaccines , vaccines for VHF-associated viruses are generally not available. Post-exposure prophylactic (preventive) ribavirin may be effective for some bunyavirus and arenavirus infections. VHF isolation guidelines dictate that all VHF patients (with the exception of dengue patients) should be cared for using strict contact precautions, including hand hygiene, double gloves, gowns, shoe and leg coverings, and face shield or goggles. Lassa, CCHF, Ebola, and Marburg viruses may be particularly prone to nosocomial (hospital-based) spread. Airborne precautions should be utilized including, at a minimum, a fit-tested , HEPA filter-equipped respirator (such as an N95 mask ), a battery-powered, air-purifying respirator, or a positive pressure supplied air respirator to be worn by personnel coming within 1.8 meter (six feet) of a VHF patient. Groups of patients should be cohorted (sequestered) to a separate building or a ward with an isolated air-handling system. Environmental decontamination is typically accomplished with hypochlorite (e.g. bleach) or phenolic disinfectants . Medical management of VHF patients may require intensive supportive care. Antiviral therapy with intravenous ribavirin may be useful in Bunyaviridae and Arenaviridae infections (specifically Lassa fever, RVF, CCHF, and HFRS due to Old World Hantavirus infection) and can be used only under an experimental protocol as IND approved by the U.S. Food and Drug Administration (FDA). Interferon may be effective in Argentine or Bolivian hemorrhagic fevers (also available only as IND). [ citation needed ]The VHF viruses are spread in a variety of ways. Some may be transmitted to humans through a respiratory route. [ citation needed ] The virus is considered by military medical planners to have a potential for aerosol dissemination, weaponization, or likelihood for confusion with similar agents that might be weaponized.

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Smallpox vaccine

AU : D The smallpox vaccine is the first vaccine to have been developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox virus. Cowpox served as a natural vaccine until the modern smallpox vaccine emerged in the 20th century. From 1958 to 1977, the World Health Organization (WHO) conducted a global vaccination campaign that eradicated smallpox , making it the only human disease to be eradicated. Although routine smallpox vaccination is no longer performed on the general public, the vaccine is still being produced to guard against bioterrorism , biological warfare , and mpox . The term vaccine derives from the Latin word for cow, reflecting the origins of smallpox vaccination. Edward Jenner referred to cowpox as variolae vaccinae (smallpox of the cow). The origins of the smallpox vaccine became murky over time, especially after Louis Pasteur developed laboratory techniques for creating vaccines in the 19th century. Allan Watt Downie demonstrated in 1939 that the modern smallpox vaccine was serologically distinct from cowpox, and vaccinia was subsequently recognized as a separate viral species. Whole-genome sequencing has revealed that vaccinia is most closely related to horsepox , and the cowpox strains found in Great Britain are the least closely related to vaccinia . As the oldest vaccine, the smallpox vaccine has gone through several generations of medical technology. From 1796 to the 1880s, the vaccine was transmitted from one person to another through arm-to-arm vaccination. Smallpox vaccine was successfully maintained in cattle starting in the 1840s, and calf lymph vaccine became the leading smallpox vaccine in the 1880s. First-generation vaccines grown on the skin of live animals were widely distributed in the 1950s–1970s to eradicate smallpox. Second-generation vaccines were grown in chorioallantoic membrane or cell cultures for greater purity, and they were used in some areas during the smallpox eradication campaign. Third-generation vaccines are based on attenuated strains of vaccinia and saw limited use prior to the eradication of smallpox. All three generations of vaccine are available in stockpiles. First and second-generation vaccines contain live unattenuated vaccinia virus and can cause serious side effects in a small percentage of recipients, including death in 1–10 people per million vaccinations. Third-generation vaccines are much safer due to the milder side effects of the attenuated vaccinia strains. Second and third-generation vaccines are still being produced, with manufacturing capacity being built up in the 2000s due to fears of bioterrorism and biological warfare. The first-generation vaccines are manufactured by growing live vaccinia virus in the skin of live animals. Most first-generation vaccines are calf lymph vaccines that were grown on the skin of cows, but other animals were also used, including sheep. The development of freeze-dried vaccine in the 1950s made it possible to preserve vaccinia virus for long periods of time without refrigeration, leading to the availability of freeze-dried vaccines such as Dryvax. : 115 The vaccine is administered by multiple puncture of the skin (scarification) with a bifurcated needle that holds vaccine solution in the fork. The skin should be cleaned with water rather than alcohol, as the alcohol could inactivate the vaccinia virus. : 292 If alcohol is used, it must be allowed to evaporate completely before the vaccine is administered. : 292 Vaccination results in a skin lesion that fills with pus and eventually crusts over. This manifestation of localized vaccinia infection is known as a vaccine "take" and demonstrates immunity to smallpox. After 2–3 weeks, the scab will fall off and leave behind a vaccine scar. First generation vaccines consist of live, unattenuated vaccinia virus. One-third of first-time vaccinees develop side effects significant enough to miss school, work, or other activities, or have difficulty sleeping. 15–20% of children receiving the vaccine for the first time develop fevers of over 102 °F (39 °C) . The vaccinia lesion can transmit the virus to other people. Rare side effects include postvaccinal encephalitis and myopericarditis. Many countries have stockpiled first generation smallpox vaccines. In a 2006 predictive analysis of casualties if there were a mass vaccination of the populations of Germany and the Netherlands, it was estimated that a total of 9.8 people in the Netherlands and 46.2 people in Germany would die from uncontrolled vaccinia infection after being vaccinated with the New York City Board of Health strain. More deaths were predicted for vaccines based other strains: Lister (55.1 Netherlands, 268.5 Germany) and Bern (303.5 Netherlands, 1,381 Germany). The second-generation vaccines consist of live vaccinia virus grown in the chorioallantoic membrane or cell culture . The second-generation vaccines are also administered through scarification with a bifurcated needle, and they carry the same side effects as the first-generation vaccinia strain that was cloned. However, the use of eggs or cell culture allows for vaccine production in a sterile environment, while first-generation vaccine contains skin bacteria from the animal that the vaccine was grown on. Ernest William Goodpasture , Alice Miles Woodruff , and G. John Buddingh grew vaccinia virus on the chorioallantoic membrane of chicken embryos in 1932. The Texas Department of Health began producing egg-based vaccine in 1939 and started using it in vaccination campaigns in 1948. : 588 Lederle Laboratories began selling its Avianized smallpox vaccine in the United States in 1959. Egg-based vaccine was also used widely in Brazil, New Zealand, and Sweden, and on a smaller scale in many other countries. Concerns about temperature stability and avian sarcoma leukosis virus prevented it from being used more widely during the eradication campaign, although no increase in leukemia was seen in Brazil and Sweden despite the presence of ASLV in the chickens. : 588 Vaccinia was first grown in cell culture in 1931 by Thomas Milton Rivers . The WHO funded work in the 1960s at the Dutch National Institute for Public Health and the Environment (RIVM) on growing the Lister/Elstree strain in rabbit kidney cells and tested it in 45,443 Indonesian children in 1973, with comparable results to the same strain of calf lymph vaccine. : 588–589 Two other cell culture vaccines were developed from the Lister strain in the 2000s: Elstree-BN (Bavarian Nordic) and VV Lister CEP (Chicken Embryo Primary, Sanofi Pasteur). Lister/Elstree-RIVM was stockpiled in the Netherlands, and Elstree-BN was sold to some European countries for stockpiles. However, Sanofi dropped its own vaccine after it acquired Acambis in 2008. ACAM2000 is a vaccine developed by Acambis , which was acquired by Sanofi Pasteur in 2008, before selling the smallpox vaccine to Emergent Biosolutions in 2017. Six strains of vaccinia were isolated from 3,000 doses of Dryvax and found to exhibit significant variation in virulence. The strain with the most similar virulence to the overall Dryvax mixture was selected and grown in MRC-5 cells to make the ACAM1000 vaccine. After a successful Phase I trial of ACAM1000, the virus was passaged three times in Vero cells to develop ACAM2000, which entered mass production at Baxter . The United States ordered over 200 million doses of ACAM2000 in 1999–2001 for its stockpile, and production is ongoing to replace expired vaccine. The third-generation vaccines are based on attenuated vaccinia viruses that are much less virulent and carry lesser side effects. The attenuated viruses may be replicating or non-replicating. Modified vaccinia Ankara (MVA, German : Modifiziertes Vakziniavirus Ankara ) is a replication-incompetent variant of vaccinia that was developed in West Germany through serial passage . The original Ankara strain of vaccinia was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich . After 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses. MVA stimulates the production of fewer antibodies than replicating vaccines. During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine. : 585 Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. In the 2000s, MVA was tested in animal models at much higher dosages. When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects. MVA-BN (also known as: Imvanex in the European Union; Imvamune in Canada; and Jynneos ) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take." A "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer. MVA-BN can also be administered intradermally to increase the number of available doses. It is safer for immunocompromised patients and those who are at risk from a vaccinia [ definition needed ] infection. [ citation needed ] MVA-BN has been approved in the European Union, Canada, and the United States. Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000. This vaccine has also been approved for use against mpox . LC16m8 is a replicating attenuated strain of vaccinia that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral vaccinia . However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take", but safety is similar to MVA. The first-generation vaccines are manufactured by growing live vaccinia virus in the skin of live animals. Most first-generation vaccines are calf lymph vaccines that were grown on the skin of cows, but other animals were also used, including sheep. The development of freeze-dried vaccine in the 1950s made it possible to preserve vaccinia virus for long periods of time without refrigeration, leading to the availability of freeze-dried vaccines such as Dryvax. : 115 The vaccine is administered by multiple puncture of the skin (scarification) with a bifurcated needle that holds vaccine solution in the fork. The skin should be cleaned with water rather than alcohol, as the alcohol could inactivate the vaccinia virus. : 292 If alcohol is used, it must be allowed to evaporate completely before the vaccine is administered. : 292 Vaccination results in a skin lesion that fills with pus and eventually crusts over. This manifestation of localized vaccinia infection is known as a vaccine "take" and demonstrates immunity to smallpox. After 2–3 weeks, the scab will fall off and leave behind a vaccine scar. First generation vaccines consist of live, unattenuated vaccinia virus. One-third of first-time vaccinees develop side effects significant enough to miss school, work, or other activities, or have difficulty sleeping. 15–20% of children receiving the vaccine for the first time develop fevers of over 102 °F (39 °C) . The vaccinia lesion can transmit the virus to other people. Rare side effects include postvaccinal encephalitis and myopericarditis. Many countries have stockpiled first generation smallpox vaccines. In a 2006 predictive analysis of casualties if there were a mass vaccination of the populations of Germany and the Netherlands, it was estimated that a total of 9.8 people in the Netherlands and 46.2 people in Germany would die from uncontrolled vaccinia infection after being vaccinated with the New York City Board of Health strain. More deaths were predicted for vaccines based other strains: Lister (55.1 Netherlands, 268.5 Germany) and Bern (303.5 Netherlands, 1,381 Germany). The second-generation vaccines consist of live vaccinia virus grown in the chorioallantoic membrane or cell culture . The second-generation vaccines are also administered through scarification with a bifurcated needle, and they carry the same side effects as the first-generation vaccinia strain that was cloned. However, the use of eggs or cell culture allows for vaccine production in a sterile environment, while first-generation vaccine contains skin bacteria from the animal that the vaccine was grown on. Ernest William Goodpasture , Alice Miles Woodruff , and G. John Buddingh grew vaccinia virus on the chorioallantoic membrane of chicken embryos in 1932. The Texas Department of Health began producing egg-based vaccine in 1939 and started using it in vaccination campaigns in 1948. : 588 Lederle Laboratories began selling its Avianized smallpox vaccine in the United States in 1959. Egg-based vaccine was also used widely in Brazil, New Zealand, and Sweden, and on a smaller scale in many other countries. Concerns about temperature stability and avian sarcoma leukosis virus prevented it from being used more widely during the eradication campaign, although no increase in leukemia was seen in Brazil and Sweden despite the presence of ASLV in the chickens. : 588 Vaccinia was first grown in cell culture in 1931 by Thomas Milton Rivers . The WHO funded work in the 1960s at the Dutch National Institute for Public Health and the Environment (RIVM) on growing the Lister/Elstree strain in rabbit kidney cells and tested it in 45,443 Indonesian children in 1973, with comparable results to the same strain of calf lymph vaccine. : 588–589 Two other cell culture vaccines were developed from the Lister strain in the 2000s: Elstree-BN (Bavarian Nordic) and VV Lister CEP (Chicken Embryo Primary, Sanofi Pasteur). Lister/Elstree-RIVM was stockpiled in the Netherlands, and Elstree-BN was sold to some European countries for stockpiles. However, Sanofi dropped its own vaccine after it acquired Acambis in 2008. ACAM2000 is a vaccine developed by Acambis , which was acquired by Sanofi Pasteur in 2008, before selling the smallpox vaccine to Emergent Biosolutions in 2017. Six strains of vaccinia were isolated from 3,000 doses of Dryvax and found to exhibit significant variation in virulence. The strain with the most similar virulence to the overall Dryvax mixture was selected and grown in MRC-5 cells to make the ACAM1000 vaccine. After a successful Phase I trial of ACAM1000, the virus was passaged three times in Vero cells to develop ACAM2000, which entered mass production at Baxter . The United States ordered over 200 million doses of ACAM2000 in 1999–2001 for its stockpile, and production is ongoing to replace expired vaccine. The third-generation vaccines are based on attenuated vaccinia viruses that are much less virulent and carry lesser side effects. The attenuated viruses may be replicating or non-replicating. Modified vaccinia Ankara (MVA, German : Modifiziertes Vakziniavirus Ankara ) is a replication-incompetent variant of vaccinia that was developed in West Germany through serial passage . The original Ankara strain of vaccinia was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich . After 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses. MVA stimulates the production of fewer antibodies than replicating vaccines. During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine. : 585 Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. In the 2000s, MVA was tested in animal models at much higher dosages. When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects. MVA-BN (also known as: Imvanex in the European Union; Imvamune in Canada; and Jynneos ) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take." A "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer. MVA-BN can also be administered intradermally to increase the number of available doses. It is safer for immunocompromised patients and those who are at risk from a vaccinia [ definition needed ] infection. [ citation needed ] MVA-BN has been approved in the European Union, Canada, and the United States. Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000. This vaccine has also been approved for use against mpox . LC16m8 is a replicating attenuated strain of vaccinia that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral vaccinia . However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take", but safety is similar to MVA. Modified vaccinia Ankara (MVA, German : Modifiziertes Vakziniavirus Ankara ) is a replication-incompetent variant of vaccinia that was developed in West Germany through serial passage . The original Ankara strain of vaccinia was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich . After 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses. MVA stimulates the production of fewer antibodies than replicating vaccines. During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine. : 585 Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. In the 2000s, MVA was tested in animal models at much higher dosages. When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects. MVA-BN (also known as: Imvanex in the European Union; Imvamune in Canada; and Jynneos ) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take." A "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer. MVA-BN can also be administered intradermally to increase the number of available doses. It is safer for immunocompromised patients and those who are at risk from a vaccinia [ definition needed ] infection. [ citation needed ] MVA-BN has been approved in the European Union, Canada, and the United States. Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000. This vaccine has also been approved for use against mpox . LC16m8 is a replicating attenuated strain of vaccinia that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral vaccinia . However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take", but safety is similar to MVA. Vaccinia is infectious, which improves its effectiveness, but causes serious complications for people with impaired immune systems (for example chemotherapy and AIDS patients) or history of eczema, and is not considered safe for pregnant women. A woman planning on conceiving should not receive smallpox immunization. Vaccines that only contain attenuated vaccinia viruses (an attenuated virus is one in which the pathogenicity has been decreased through serial passage ) have been proposed, but some researchers [ who? ] have questioned the possible effectiveness of such a vaccine. According to the US Centers for Disease Control and Prevention (CDC), "within 3 days of being exposed to the virus, the vaccine might protect you from getting the disease. If you still get the disease, you might get much less sick than an unvaccinated person would. Within 4 to 7 days of being exposed to the virus, the vaccine likely gives you some protection from the disease. If you still get the disease, you might not get as sick as an unvaccinated person would." In May 2007, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the U.S. Food and Drug Administration (FDA) voted unanimously that a new live virus vaccine produced by Acambis , ACAM2000 , is both safe and effective for use in persons at high risk of exposure to smallpox virus. However, due to the high rate of serious adverse effects, the vaccine will only be made available to the CDC for the Strategic National Stockpile . Since smallpox has been eradicated, the public is not routinely vaccinated against the disease. The World Health Organization maintained a stockpile of 200 million doses in 1980, to guard against reemergence of the disease, but 99% of the stockpile was destroyed in the late 1980s when smallpox failed to return. After the September 11 attacks in 2001, many governments began building up vaccine stockpiles again for fear of bioterrorism. Several companies sold off their stockpiles of vaccines manufactured in the 1970s, and production of smallpox vaccines resumed. Aventis Pasteur discovered a stockpile from the 1950s and donated it to the U.S. government. Stockpiles of newer vaccines must be repurchased periodically since they carry expiration dates. The United States had received 269 million doses of ACAM2000 and 28 million doses of MVA-BN by 2019, but only 100 million doses of ACAM2000 and 65,000 doses of MVA-BN were still available from the stockpile at the start of the 2022 monkeypox outbreak . First-generation vaccines have no specified expiration date and remain viable indefinitely in deep freeze. The U.S. stockpile of WetVax was manufactured in 1956–1957 and maintained since then at −4 °F (−20 °C) , and it was still effective when tested in 2004. Replicating vaccines also remain effective even at 1:10 dilution, so a limited number of doses can be stretched to cover a much larger population. 300,000 ACAM2000 (2nd) 2.4 million various (1st)The mortality of the severe form of smallpox – variola major – was very high without vaccination, up to 35% in some outbreaks. A method of inducing immunity known as inoculation, insufflation or " variolation " was practiced before the development of a modern vaccine and likely occurred in Africa and China well before the practice arrived in Europe. It may also have occurred in India, but this is disputed; other investigators contend the ancient Sanskrit medical texts of India do not describe these techniques. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Douzhen xinfa (痘疹心法) published in 1549. Inoculation for smallpox does not appear to have been widespread in China until the reign era of the Longqing Emperor (r. 1567–1572) during the Ming Dynasty . In China, powdered smallpox scabs were blown up the noses of the healthy. The patients would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia . Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". Variolation was also practiced throughout the latter half of the 17th century by physicians in Turkey , Persia , and Africa. In 1714 and 1716, two reports of the Ottoman Empire Turkish method of inoculation were made to the Royal Society in England, by Emmanuel Timoni, a doctor affiliated with the British Embassy in Constantinople , and Giacomo Pylarini . Source material tells us on Lady Mary Wortley Montagu; "When Lady Mary was in the Ottoman Empire, she discovered the local practice of inoculation against smallpox called variolation." In 1718 she had her son, aged five variolated. He recovered quickly. She returned to London and had her daughter variolated in 1721 by Charles Maitland , during an epidemic of smallpox. This encouraged the British Royal Family to take an interest and a trial of variolation was carried out on prisoners in Newgate Prison . This was successful and in 1722 Caroline of Ansbach , the Princess of Wales, allowed Maitland to vaccinate her children. The success of these variolations assured the British people that the procedure was safe. ...scarred the wrists, legs, and forehead of the patient, placed a fresh and kindly pock in each incision and bound it there for eight or ten days, after this time the patient was credibly informed. The patient would then develop a mild case [of smallpox], recover, and thereafter be immune. —Dr. Peter Kennedy Stimulated by a severe epidemic, variolation was first employed in North America in 1721. The procedure had been known in Boston since 1706, when preacher Cotton Mather learned it from Onesimus , a man he held as a slave, who – like many of his peers – had been inoculated in Africa before they were kidnapped. This practice was widely criticized at first. However, a limited trial showed six deaths occurred out of 244 who were variolated (2.5%), while 844 out of 5980 died of natural disease (14%), and the process was widely adopted throughout the colonies. The inoculation technique was documented as having a mortality rate of only one in a thousand. Two years after Kennedy's description appeared, March 1718, Dr. Charles Maitland successfully inoculated the five-year-old son of the British ambassador to the Turkish court under orders from the ambassador's wife Lady Mary Wortley Montagu , who four years later introduced the practice to England. An account from letter by Lady Mary Wortley Montagu to Sarah Chiswell, dated 1 April 1717, from the Turkish Embassy describes this treatment: The small-pox so fatal and so general amongst us is here entirely harmless by the invention of ingrafting (which is the term they give it). There is a set of old women who make it their business to perform the operation. Every autumn in the month of September, when the great heat is abated, people send to one another to know if any of their family has a mind to have the small-pox. They make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of small-pox and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much venom as can lye upon the head of her needle, and after binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. … The children or young patients play together all the rest of the day and are in perfect health till the eighth. Then the fever begins to seize them and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before the illness. … There is no example of any one that has died in it, and you may believe I am very well satisfied of the safety of the experiment since I intend to try it on my dear little son. I am patriot enough to take pains to bring this useful invention into fashion in England, and I should not fail to write to some of our doctors very particularly about it if I knew any one of them that I thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind, but that distemper is too beneficial to them not to expose to all their resentment the hardy wight that should undertake to put an end to it. Perhaps if I live to return I may, however, have courage to war with them. In the early empirical days of vaccination, before Louis Pasteur 's work on establishing the germ theory and Joseph Lister 's on antisepsis and asepsis, there was considerable cross-infection. William Woodville , one of the early vaccinators and director of the London Smallpox Hospital is thought to have contaminated the cowpox matter – the vaccine – with smallpox matter and this essentially produced variolation. Other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle. During the earlier days of empirical experimentation in 1758, American Calvinist Jonathan Edwards died from a smallpox inoculation. Some of the earliest statistical and epidemiological studies were performed by James Jurin in 1727 and Daniel Bernoulli in 1766. In 1768, Dr John Fewster reported that variolation induced no reaction in persons who had had cowpox. Edward Jenner was born in Berkeley , England as an orphan. As a young child, Jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. Fed purgative medicine and going through the bloodletting process, Jenner was put in one of the variolation stables until he recovered. At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later surgeon George Hardwick in nearby Sodbury . He observed that people who caught cowpox while working with cattle were known not to catch smallpox. Jenner assumed a causal connection but the idea was not taken up at that time. From 1770 to 1772 Jenner received advanced training in London at St Georges Hospital and as the private pupil of John Hunter , then returned to set up practice in Berkeley. Perhaps there was already an informal public understanding of some connection between disease resistance and working with cattle. The "beautiful milkmaid " seems to have been a frequent image in the art and literature of this period. But it is known for certain that in the years following 1770, at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791) tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans. Jenner sent a paper reporting his observations to the Royal Society in April 1797. It was not submitted formally and there is no mention of it in the Society's records. Jenner had sent the paper informally to Sir Joseph Banks , the Society's president, who asked Everard Home for his views. Reviews of his rejected report, published for the first time in 1999, were skeptical and called for further vaccinations. Additional vaccinations were performed and in 1798 Jenner published his work entitled An Inquiry into the Causes and Effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire and Known by the Name of Cow Pox. It was an analysis of 23 cases including several individuals who had resisted natural exposure after previous cowpox. It is not known how many Jenner vaccinated or challenged by inoculation with smallpox virus; e.g. Case 21 included 'several children and adults'. Crucially all of at least four whom Jenner deliberately inoculated with smallpox virus resisted it. These included the first and last patients in a series of arm-to-arm transfers. He concluded that cowpox inoculation was a safe alternative to smallpox inoculation, but rashly claimed that the protective effect was lifelong. This last proved to be incorrect. Jenner also tried to distinguish between 'True' cowpox which produced the desired result and 'Spurious' cowpox which was ineffective and/or produced severe reaction. Modern research suggests Jenner was trying to distinguish between effects caused by what would now [ when? ] be recognised as non-infectious vaccine, a different virus (e.g. paravaccinia /milker's nodes), or contaminating bacterial pathogens. This caused confusion at the time, but would become important criteria in vaccine development. A further source of confusion was Jenner's belief that fully effective vaccine obtained from cows originated in an equine disease, which he mistakenly referred to as grease . This was criticised at the time but vaccines derived from horsepox were soon introduced and later contributed to the complicated problem of the origin of vaccinia virus , the virus in present-day vaccine. : 165–78 The introduction of the vaccine to the New World took place in Trinity, Newfoundland , in 1798 by Dr. John Clinch , boyhood friend and medical colleague of Jenner. The first smallpox vaccine in the United States was administered in 1799. The physician Valentine Seaman gave his children a smallpox vaccination using a serum acquired from Jenner. By 1800, Jenner's work had been published in all the major European languages and had reached Benjamin Waterhouse in the United States – an indication of rapid spread and deep interest. : 262–67 Despite some concern about the safety of vaccination the mortality using carefully selected vaccine was close to zero, and it was soon in use all over Europe and the United States. In 1804 the Balmis Expedition , an official Spanish mission commanded by Francisco Javier de Balmis , sailed to spread the vaccine throughout the Spanish Empire, first to the Canary Islands and on to Spanish Central America. While his deputy, José Salvany, took vaccine to the west and east coasts of Spanish South America, Balmis sailed to Manila in the Philippines and on to Canton and Macao on the Chinese coast. He returned to Spain in 1806. The vaccine was not carried in the form of flasks, but in the form of 22 orphaned boys, who were 'carriers' of the live cowpox virus. After arrival, "other Spanish governors and doctors used enslaved girls to move the virus between islands, using lymph fluid harvested from them to inoculate their local populations". Napoleon was an early proponent of smallpox vaccination and ordered that army recruits be given the vaccine. Additionally a vaccination program was created for the French Army and his Imperial Guard . In 1811 he had his son, Napoleon II , vaccinated after his birth. By 1815 about half of French children were vaccinated and by the end of the Napoleonic Empire smallpox deaths accounted for 1.8% of deaths, as opposed to the 4.8% of deaths it accounted for at the time of the French Revolution . The first state to introduce compulsory vaccinations was the Principality of Lucca and Piombino on 25 September 1806. On 26 August 1807, Bavaria introduced a similar measure. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816, England in 1867 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. The question of who first tried cowpox inoculation/vaccination cannot be answered with certainty. Most, but still limited, information is available for Benjamin Jesty , Peter Plett and John Fewster . In 1774 Jesty, a farmer of Yetminster in Dorset , observing that the two milkmaids living with his family were immune to smallpox, inoculated his family with cowpox to protect them from smallpox. He attracted a certain amount of local criticism and ridicule at the time then interest waned. Attention was later drawn to Jesty, and he was brought to London in 1802 by critics jealous of Jenner's prominence at a time when he was applying to Parliament for financial reward. During 1790–92 Peter Plett, a teacher from Holstein , reported limited results of cowpox inoculation to the Medical Faculty of the University of Kiel . However, the Faculty favoured variolation and took no action. John Fewster, a surgeon friend of Jenner's from nearby Thornbury, discussed the possibility of cowpox inoculation at meetings as early as 1765. He may have done some cowpox inoculations in 1796 at about the same time that Jenner vaccinated Phipps. However, Fewster, who had a flourishing variolation practice, may have considered this option but used smallpox instead. He thought vaccination offered no advantage over variolation, but maintained friendly contact with Jenner and certainly made no claim of priority for vaccination when critics attacked Jenner's reputation. It seems clear that the idea of using cowpox instead of smallpox for inoculation was considered, and actually tried in the late 18th century, and not just by the medical profession. Therefore, Jenner was not the first to try cowpox inoculation. However, he was the first to publish his evidence and distribute vaccine freely, provide information on selection of suitable material, and maintain it by arm-to-arm transfer. The authors of the official World Health Organization (WHO) account Smallpox and its Eradication assessing Jenner's role wrote: : 264 Publication of the Inquiry and the subsequent energetic promulgation by Jenner of the idea of vaccination with a virus other than variola virus constituted a watershed in the control of smallpox for which he, more than anyone else deserves the credit. As vaccination spread, some European countries made it compulsory. Concern about its safety led to opposition and then repeal of legislation in some instances. : 236–40 Compulsory infant vaccination was introduced in England by the 1853 Vaccination Act . By 1871, parents could be fined for non-compliance, and then imprisoned for non-payment. : 202–13 This intensified opposition, and the 1898 Vaccination Act introduced a conscience clause. This allowed exemption on production of a certificate of conscientious objection signed by two magistrates. Such certificates were not always easily obtained and a further Act in 1907 allowed exemption by a statutory declaration which could not be refused. Although theoretically still compulsory, the 1907 Act effectively marked the end of compulsory infant vaccination in England. : 233–38 In the United States vaccination was regulated by individual states, the first to impose compulsory vaccination being Massachusetts in 1809. There then followed sequences of compulsion, opposition and repeal in various states. By 1930 Arizona, Utah, North Dakota and Minnesota prohibited compulsory vaccination, 35 states allowed regulation by local authorities, or had no legislation affecting vaccination, whilst in ten states, including Washington, D.C. and Massachusetts, infant vaccination was compulsory. : 292–93 Compulsory infant vaccination was regulated by only allowing access to school for those who had been vaccinated. Those seeking to enforce compulsory vaccination argued that the public good overrode personal freedom, a view supported by the U.S. Supreme Court in Jacobson v. Massachusetts in 1905, a landmark ruling which set a precedent for cases dealing with personal freedom and the public good. Louis T. Wright, an African-American Harvard Medical School graduate (1915), introduced, while serving in the Army during World War I , intradermal, smallpox vaccination for the soldiers. Until the end of the 19th century, vaccination was performed either directly with vaccine produced on the skin of calves or, particularly in England, with vaccine obtained from the calf but then maintained by arm-to-arm transfer; initially in both cases vaccine could be dried on ivory points for short-term storage or transport but increasing use was made of glass capillary tubes for this purpose towards the end of the century. During this period there were no adequate methods for assessing the safety of the vaccine and there were instances of contaminated vaccine transmitting infections such as erysipelas, tetanus, septicaemia and tuberculosis. In the case of arm-to-arm transfer there was also the risk of transmitting syphilis. Although this did occur occasionally, estimated as 750 cases in 100 million vaccinations, : 122 some critics of vaccination e.g. Charles Creighton believed that uncontaminated vaccine itself was a cause of syphilis. Smallpox vaccine was the only vaccine available during this period, and so the determined opposition to it initiated a number of vaccine controversies that spread to other vaccines and into the 21st century. [ citation needed ] Sydney Arthur Monckton Copeman , an English Government bacteriologist interested in smallpox vaccine investigated the effects on the bacteria in it of various treatments, including glycerine . Glycerine was sometimes used simply as a diluent by some continental vaccine producers. However, Copeman found that vaccine suspended in 50% chemically pure glycerine and stored under controlled conditions contained very few "extraneous" bacteria and produced satisfactory vaccinations. He later reported that glycerine killed the causative organisms of erysipelas and tuberculosis when they were added to the vaccine in "considerable quantity", and that his method was widely used on the continent. In 1896, Copeman was asked to supply "extra good calf vaccine" to vaccinate the future Edward VIII . Vaccine produced by Copeman's method was the only type issued free to public vaccinators by the English Government Vaccine Establishment from 1899. At the same time the 1898 Vaccination Act banned arm-to-arm vaccination, thus preventing transmission of syphilis by this vaccine. However, private practitioners had to purchase vaccine from commercial producers. Although proper use of glycerine reduced bacterial contamination considerably the crude starting material, scraped from the skin of infected calves, was always heavily contaminated and no vaccine was totally free from bacteria. A survey of vaccines in 1900 found wide variations in bacterial contamination. Vaccine issued by the Government Vaccine Establishment contained 5,000 bacteria per gram, while commercial vaccines contained up to 100,000 per gram. The level of bacterial contamination remained unregulated until the Therapeutic Substances Act, 1925 set an upper limit of 5,000 per gram, and rejected any batch of vaccine found to contain the causative organisms of erysipelas or wound infections. Unfortunately glycerolated vaccine soon lost its potency at ambient temperatures which restricted its use in tropical climates. However, it remained in use into the 1970s where a satisfactory cold chain was available. Animals continued to be widely used by vaccine producers during the smallpox eradication campaign. A WHO survey of 59 producers, some of whom used more than one source of vaccine, found that 39 used calves, 12 used sheep and 6 used water buffalo, whilst only 3 made vaccine in cell culture and 3 in embryonated hens' eggs. : 543–45 English vaccine was occasionally made in sheep during World War I but from 1946 only sheep were used. In the late 1940s and early 1950s, Leslie Collier , an English microbiologist working at the Lister Institute of Preventive Medicine , developed a method for producing a heat-stable freeze-dried vaccine in powdered form. Collier added 0.5% phenol to the vaccine to reduce the number of bacterial contaminants but the key stage was to add 5% peptone to the liquid vaccine before it was dispensed into ampoules. This protected the virus during the freeze drying process. After drying the ampoules were sealed under nitrogen. Like other vaccines, once reconstituted it became ineffective after 1–2 days at ambient temperatures. However, the dried vaccine was 100% effective when reconstituted after 6 months storage at 37 °C (99 °F) allowing it to be transported to, and stored in, remote tropical areas. Collier's method was increasingly used and, with minor modifications, became the standard for vaccine production adopted by the WHO Smallpox Eradication Unit when it initiated its global smallpox eradication campaign in 1967, at which time 23 of 59 manufacturers were using the Lister strain. : 545, 550 In a letter about landmarks in the history of smallpox vaccine, written to and quoted from by Derrick Baxby , Donald Henderson , chief of the Smallpox Eradication Unit from 1967 to 1977 wrote; "Copeman and Collier made an enormous contribution for which neither, in my opinion ever received due credit". Smallpox vaccine was inoculated by scratches into the superficial layers of the skin, with a wide variety of instruments used to achieve this. They ranged from simple needles to multi-pointed and multi-bladed spring-operated instruments specifically designed for the purpose. A major contribution to smallpox vaccination was made in the 1960s by Benjamin Rubin , an American microbiologist working for Wyeth Laboratories. Based on initial tests with textile needles with the eyes cut off transversely half-way he developed the bifurcated needle . This was a sharpened two-prong fork designed to hold one dose of reconstituted freeze-dried vaccine by capillarity. Easy to use with minimum training, cheap to produce ($5 per 1000), using one quarter as much vaccine as other methods, and repeatedly re-usable after flame sterilization, it was used globally in the WHO Smallpox Eradication Campaign from 1968. : 472–73, 568–72 Rubin estimated that it was used to do 200 million vaccinations per year during the last years of the campaign. Those closely involved in the campaign were awarded the "Order of the Bifurcated Needle". This, a personal initiative by Donald Henderson, was a lapel badge, designed and made by his daughter, formed from the needle shaped to form an "O". This represented "Target Zero", the objective of the campaign. Smallpox was eradicated by a massive international search for outbreaks, backed up with a vaccination program, starting in 1967. It was organised and co-ordinated by a World Health Organization (WHO) unit, set up and headed by Donald Henderson . The last case in the Americas occurred in 1971 (Brazil), south-east Asia (Indonesia) in 1972, and on the Indian subcontinent in 1975 (Bangladesh). After two years of intensive searches, what proved to be the last endemic case anywhere in the world occurred in Somalia, in October 1977. : 526–37 A Global Commission for the Certification of Smallpox Eradication chaired by Frank Fenner examined the evidence from, and visited where necessary, all countries where smallpox had been endemic. In December 1979 they concluded that smallpox had been eradicated; a conclusion endorsed by the WHO General Assembly in May 1980. : 1261–62 However, even as the disease was being eradicated there still remained stocks of smallpox virus in many laboratories. Accelerated by two cases of smallpox in 1978, one fatal ( Janet Parker ), caused by an accidental and unexplained containment breach at a laboratory at the University of Birmingham Medical School , the WHO ensured that known stocks of smallpox virus were either destroyed or moved to safer laboratories. By 1979, only four laboratories were known to have smallpox virus. All English stocks held at St Mary's Hospital, London were transferred to more secure facilities at Porton Down and then to the U.S. at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in 1982, and all South African stocks were destroyed in 1983. By 1984, the only known stocks were kept at the CDC in the U.S. and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia . : 1273–76 These states report that their repositories are for possible anti- bioweaponry research and insurance if some obscure reservoir of natural smallpox is discovered in the future. [ citation needed ] Among more than 270,000 US military service members vaccinated with smallpox vaccine between December 2002, and March 2003, eighteen cases of probable myopericarditis were reported (all in first-time vaccinees who received the NYCBOH strain of vaccinia virus), an incidence of 7.8 per 100,000 during the 30 days they were observed. All cases were in young, otherwise healthy adult white men and all survived. In 2002, the United States government started a program to vaccinate 500,000 volunteer health care professionals throughout the country. Recipients were healthcare workers who would be first-line responders in the event of a bioterrorist attack. Many healthcare workers refused or did not pursue vaccination, worried about vaccine side effects, compensation and liability. Most did not see an immediate need for the vaccine. Some healthcare systems refused to participate, worried about becoming a destination for smallpox patients in the event of an epidemic. Fewer than 40,000 actually received the vaccine. On 21 April 2022, Public Services and Procurement Canada published a notice of tender seeking to stockpile 500,000 doses of smallpox vaccine in order to protect against a potential accidental or intentional release of the eradicated virus. On 6 May, the contract was awarded to Bavarian Nordic for their Imvamune vaccine. These were deployed by the Public Health Agency of Canada for targeted vaccination in response to the 2022 monkeypox outbreak . The mortality of the severe form of smallpox – variola major – was very high without vaccination, up to 35% in some outbreaks. A method of inducing immunity known as inoculation, insufflation or " variolation " was practiced before the development of a modern vaccine and likely occurred in Africa and China well before the practice arrived in Europe. It may also have occurred in India, but this is disputed; other investigators contend the ancient Sanskrit medical texts of India do not describe these techniques. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Douzhen xinfa (痘疹心法) published in 1549. Inoculation for smallpox does not appear to have been widespread in China until the reign era of the Longqing Emperor (r. 1567–1572) during the Ming Dynasty . In China, powdered smallpox scabs were blown up the noses of the healthy. The patients would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers . According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia . Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". Variolation was also practiced throughout the latter half of the 17th century by physicians in Turkey , Persia , and Africa. In 1714 and 1716, two reports of the Ottoman Empire Turkish method of inoculation were made to the Royal Society in England, by Emmanuel Timoni, a doctor affiliated with the British Embassy in Constantinople , and Giacomo Pylarini . Source material tells us on Lady Mary Wortley Montagu; "When Lady Mary was in the Ottoman Empire, she discovered the local practice of inoculation against smallpox called variolation." In 1718 she had her son, aged five variolated. He recovered quickly. She returned to London and had her daughter variolated in 1721 by Charles Maitland , during an epidemic of smallpox. This encouraged the British Royal Family to take an interest and a trial of variolation was carried out on prisoners in Newgate Prison . This was successful and in 1722 Caroline of Ansbach , the Princess of Wales, allowed Maitland to vaccinate her children. The success of these variolations assured the British people that the procedure was safe. ...scarred the wrists, legs, and forehead of the patient, placed a fresh and kindly pock in each incision and bound it there for eight or ten days, after this time the patient was credibly informed. The patient would then develop a mild case [of smallpox], recover, and thereafter be immune. —Dr. Peter Kennedy Stimulated by a severe epidemic, variolation was first employed in North America in 1721. The procedure had been known in Boston since 1706, when preacher Cotton Mather learned it from Onesimus , a man he held as a slave, who – like many of his peers – had been inoculated in Africa before they were kidnapped. This practice was widely criticized at first. However, a limited trial showed six deaths occurred out of 244 who were variolated (2.5%), while 844 out of 5980 died of natural disease (14%), and the process was widely adopted throughout the colonies. The inoculation technique was documented as having a mortality rate of only one in a thousand. Two years after Kennedy's description appeared, March 1718, Dr. Charles Maitland successfully inoculated the five-year-old son of the British ambassador to the Turkish court under orders from the ambassador's wife Lady Mary Wortley Montagu , who four years later introduced the practice to England. An account from letter by Lady Mary Wortley Montagu to Sarah Chiswell, dated 1 April 1717, from the Turkish Embassy describes this treatment: The small-pox so fatal and so general amongst us is here entirely harmless by the invention of ingrafting (which is the term they give it). There is a set of old women who make it their business to perform the operation. Every autumn in the month of September, when the great heat is abated, people send to one another to know if any of their family has a mind to have the small-pox. They make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of small-pox and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much venom as can lye upon the head of her needle, and after binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. … The children or young patients play together all the rest of the day and are in perfect health till the eighth. Then the fever begins to seize them and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before the illness. … There is no example of any one that has died in it, and you may believe I am very well satisfied of the safety of the experiment since I intend to try it on my dear little son. I am patriot enough to take pains to bring this useful invention into fashion in England, and I should not fail to write to some of our doctors very particularly about it if I knew any one of them that I thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind, but that distemper is too beneficial to them not to expose to all their resentment the hardy wight that should undertake to put an end to it. Perhaps if I live to return I may, however, have courage to war with them. In the early empirical days of vaccination, before Louis Pasteur 's work on establishing the germ theory and Joseph Lister 's on antisepsis and asepsis, there was considerable cross-infection. William Woodville , one of the early vaccinators and director of the London Smallpox Hospital is thought to have contaminated the cowpox matter – the vaccine – with smallpox matter and this essentially produced variolation. Other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle. During the earlier days of empirical experimentation in 1758, American Calvinist Jonathan Edwards died from a smallpox inoculation. Some of the earliest statistical and epidemiological studies were performed by James Jurin in 1727 and Daniel Bernoulli in 1766. In 1768, Dr John Fewster reported that variolation induced no reaction in persons who had had cowpox. Edward Jenner was born in Berkeley , England as an orphan. As a young child, Jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. Fed purgative medicine and going through the bloodletting process, Jenner was put in one of the variolation stables until he recovered. At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later surgeon George Hardwick in nearby Sodbury . He observed that people who caught cowpox while working with cattle were known not to catch smallpox. Jenner assumed a causal connection but the idea was not taken up at that time. From 1770 to 1772 Jenner received advanced training in London at St Georges Hospital and as the private pupil of John Hunter , then returned to set up practice in Berkeley. Perhaps there was already an informal public understanding of some connection between disease resistance and working with cattle. The "beautiful milkmaid " seems to have been a frequent image in the art and literature of this period. But it is known for certain that in the years following 1770, at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791) tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans. Jenner sent a paper reporting his observations to the Royal Society in April 1797. It was not submitted formally and there is no mention of it in the Society's records. Jenner had sent the paper informally to Sir Joseph Banks , the Society's president, who asked Everard Home for his views. Reviews of his rejected report, published for the first time in 1999, were skeptical and called for further vaccinations. Additional vaccinations were performed and in 1798 Jenner published his work entitled An Inquiry into the Causes and Effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire and Known by the Name of Cow Pox. It was an analysis of 23 cases including several individuals who had resisted natural exposure after previous cowpox. It is not known how many Jenner vaccinated or challenged by inoculation with smallpox virus; e.g. Case 21 included 'several children and adults'. Crucially all of at least four whom Jenner deliberately inoculated with smallpox virus resisted it. These included the first and last patients in a series of arm-to-arm transfers. He concluded that cowpox inoculation was a safe alternative to smallpox inoculation, but rashly claimed that the protective effect was lifelong. This last proved to be incorrect. Jenner also tried to distinguish between 'True' cowpox which produced the desired result and 'Spurious' cowpox which was ineffective and/or produced severe reaction. Modern research suggests Jenner was trying to distinguish between effects caused by what would now [ when? ] be recognised as non-infectious vaccine, a different virus (e.g. paravaccinia /milker's nodes), or contaminating bacterial pathogens. This caused confusion at the time, but would become important criteria in vaccine development. A further source of confusion was Jenner's belief that fully effective vaccine obtained from cows originated in an equine disease, which he mistakenly referred to as grease . This was criticised at the time but vaccines derived from horsepox were soon introduced and later contributed to the complicated problem of the origin of vaccinia virus , the virus in present-day vaccine. : 165–78 The introduction of the vaccine to the New World took place in Trinity, Newfoundland , in 1798 by Dr. John Clinch , boyhood friend and medical colleague of Jenner. The first smallpox vaccine in the United States was administered in 1799. The physician Valentine Seaman gave his children a smallpox vaccination using a serum acquired from Jenner. By 1800, Jenner's work had been published in all the major European languages and had reached Benjamin Waterhouse in the United States – an indication of rapid spread and deep interest. : 262–67 Despite some concern about the safety of vaccination the mortality using carefully selected vaccine was close to zero, and it was soon in use all over Europe and the United States. In 1804 the Balmis Expedition , an official Spanish mission commanded by Francisco Javier de Balmis , sailed to spread the vaccine throughout the Spanish Empire, first to the Canary Islands and on to Spanish Central America. While his deputy, José Salvany, took vaccine to the west and east coasts of Spanish South America, Balmis sailed to Manila in the Philippines and on to Canton and Macao on the Chinese coast. He returned to Spain in 1806. The vaccine was not carried in the form of flasks, but in the form of 22 orphaned boys, who were 'carriers' of the live cowpox virus. After arrival, "other Spanish governors and doctors used enslaved girls to move the virus between islands, using lymph fluid harvested from them to inoculate their local populations". Napoleon was an early proponent of smallpox vaccination and ordered that army recruits be given the vaccine. Additionally a vaccination program was created for the French Army and his Imperial Guard . In 1811 he had his son, Napoleon II , vaccinated after his birth. By 1815 about half of French children were vaccinated and by the end of the Napoleonic Empire smallpox deaths accounted for 1.8% of deaths, as opposed to the 4.8% of deaths it accounted for at the time of the French Revolution . The first state to introduce compulsory vaccinations was the Principality of Lucca and Piombino on 25 September 1806. On 26 August 1807, Bavaria introduced a similar measure. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816, England in 1867 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate. The question of who first tried cowpox inoculation/vaccination cannot be answered with certainty. Most, but still limited, information is available for Benjamin Jesty , Peter Plett and John Fewster . In 1774 Jesty, a farmer of Yetminster in Dorset , observing that the two milkmaids living with his family were immune to smallpox, inoculated his family with cowpox to protect them from smallpox. He attracted a certain amount of local criticism and ridicule at the time then interest waned. Attention was later drawn to Jesty, and he was brought to London in 1802 by critics jealous of Jenner's prominence at a time when he was applying to Parliament for financial reward. During 1790–92 Peter Plett, a teacher from Holstein , reported limited results of cowpox inoculation to the Medical Faculty of the University of Kiel . However, the Faculty favoured variolation and took no action. John Fewster, a surgeon friend of Jenner's from nearby Thornbury, discussed the possibility of cowpox inoculation at meetings as early as 1765. He may have done some cowpox inoculations in 1796 at about the same time that Jenner vaccinated Phipps. However, Fewster, who had a flourishing variolation practice, may have considered this option but used smallpox instead. He thought vaccination offered no advantage over variolation, but maintained friendly contact with Jenner and certainly made no claim of priority for vaccination when critics attacked Jenner's reputation. It seems clear that the idea of using cowpox instead of smallpox for inoculation was considered, and actually tried in the late 18th century, and not just by the medical profession. Therefore, Jenner was not the first to try cowpox inoculation. However, he was the first to publish his evidence and distribute vaccine freely, provide information on selection of suitable material, and maintain it by arm-to-arm transfer. The authors of the official World Health Organization (WHO) account Smallpox and its Eradication assessing Jenner's role wrote: : 264 Publication of the Inquiry and the subsequent energetic promulgation by Jenner of the idea of vaccination with a virus other than variola virus constituted a watershed in the control of smallpox for which he, more than anyone else deserves the credit. As vaccination spread, some European countries made it compulsory. Concern about its safety led to opposition and then repeal of legislation in some instances. : 236–40 Compulsory infant vaccination was introduced in England by the 1853 Vaccination Act . By 1871, parents could be fined for non-compliance, and then imprisoned for non-payment. : 202–13 This intensified opposition, and the 1898 Vaccination Act introduced a conscience clause. This allowed exemption on production of a certificate of conscientious objection signed by two magistrates. Such certificates were not always easily obtained and a further Act in 1907 allowed exemption by a statutory declaration which could not be refused. Although theoretically still compulsory, the 1907 Act effectively marked the end of compulsory infant vaccination in England. : 233–38 In the United States vaccination was regulated by individual states, the first to impose compulsory vaccination being Massachusetts in 1809. There then followed sequences of compulsion, opposition and repeal in various states. By 1930 Arizona, Utah, North Dakota and Minnesota prohibited compulsory vaccination, 35 states allowed regulation by local authorities, or had no legislation affecting vaccination, whilst in ten states, including Washington, D.C. and Massachusetts, infant vaccination was compulsory. : 292–93 Compulsory infant vaccination was regulated by only allowing access to school for those who had been vaccinated. Those seeking to enforce compulsory vaccination argued that the public good overrode personal freedom, a view supported by the U.S. Supreme Court in Jacobson v. Massachusetts in 1905, a landmark ruling which set a precedent for cases dealing with personal freedom and the public good. Louis T. Wright, an African-American Harvard Medical School graduate (1915), introduced, while serving in the Army during World War I , intradermal, smallpox vaccination for the soldiers. Until the end of the 19th century, vaccination was performed either directly with vaccine produced on the skin of calves or, particularly in England, with vaccine obtained from the calf but then maintained by arm-to-arm transfer; initially in both cases vaccine could be dried on ivory points for short-term storage or transport but increasing use was made of glass capillary tubes for this purpose towards the end of the century. During this period there were no adequate methods for assessing the safety of the vaccine and there were instances of contaminated vaccine transmitting infections such as erysipelas, tetanus, septicaemia and tuberculosis. In the case of arm-to-arm transfer there was also the risk of transmitting syphilis. Although this did occur occasionally, estimated as 750 cases in 100 million vaccinations, : 122 some critics of vaccination e.g. Charles Creighton believed that uncontaminated vaccine itself was a cause of syphilis. Smallpox vaccine was the only vaccine available during this period, and so the determined opposition to it initiated a number of vaccine controversies that spread to other vaccines and into the 21st century. [ citation needed ] Sydney Arthur Monckton Copeman , an English Government bacteriologist interested in smallpox vaccine investigated the effects on the bacteria in it of various treatments, including glycerine . Glycerine was sometimes used simply as a diluent by some continental vaccine producers. However, Copeman found that vaccine suspended in 50% chemically pure glycerine and stored under controlled conditions contained very few "extraneous" bacteria and produced satisfactory vaccinations. He later reported that glycerine killed the causative organisms of erysipelas and tuberculosis when they were added to the vaccine in "considerable quantity", and that his method was widely used on the continent. In 1896, Copeman was asked to supply "extra good calf vaccine" to vaccinate the future Edward VIII . Vaccine produced by Copeman's method was the only type issued free to public vaccinators by the English Government Vaccine Establishment from 1899. At the same time the 1898 Vaccination Act banned arm-to-arm vaccination, thus preventing transmission of syphilis by this vaccine. However, private practitioners had to purchase vaccine from commercial producers. Although proper use of glycerine reduced bacterial contamination considerably the crude starting material, scraped from the skin of infected calves, was always heavily contaminated and no vaccine was totally free from bacteria. A survey of vaccines in 1900 found wide variations in bacterial contamination. Vaccine issued by the Government Vaccine Establishment contained 5,000 bacteria per gram, while commercial vaccines contained up to 100,000 per gram. The level of bacterial contamination remained unregulated until the Therapeutic Substances Act, 1925 set an upper limit of 5,000 per gram, and rejected any batch of vaccine found to contain the causative organisms of erysipelas or wound infections. Unfortunately glycerolated vaccine soon lost its potency at ambient temperatures which restricted its use in tropical climates. However, it remained in use into the 1970s where a satisfactory cold chain was available. Animals continued to be widely used by vaccine producers during the smallpox eradication campaign. A WHO survey of 59 producers, some of whom used more than one source of vaccine, found that 39 used calves, 12 used sheep and 6 used water buffalo, whilst only 3 made vaccine in cell culture and 3 in embryonated hens' eggs. : 543–45 English vaccine was occasionally made in sheep during World War I but from 1946 only sheep were used. In the late 1940s and early 1950s, Leslie Collier , an English microbiologist working at the Lister Institute of Preventive Medicine , developed a method for producing a heat-stable freeze-dried vaccine in powdered form. Collier added 0.5% phenol to the vaccine to reduce the number of bacterial contaminants but the key stage was to add 5% peptone to the liquid vaccine before it was dispensed into ampoules. This protected the virus during the freeze drying process. After drying the ampoules were sealed under nitrogen. Like other vaccines, once reconstituted it became ineffective after 1–2 days at ambient temperatures. However, the dried vaccine was 100% effective when reconstituted after 6 months storage at 37 °C (99 °F) allowing it to be transported to, and stored in, remote tropical areas. Collier's method was increasingly used and, with minor modifications, became the standard for vaccine production adopted by the WHO Smallpox Eradication Unit when it initiated its global smallpox eradication campaign in 1967, at which time 23 of 59 manufacturers were using the Lister strain. : 545, 550 In a letter about landmarks in the history of smallpox vaccine, written to and quoted from by Derrick Baxby , Donald Henderson , chief of the Smallpox Eradication Unit from 1967 to 1977 wrote; "Copeman and Collier made an enormous contribution for which neither, in my opinion ever received due credit". Smallpox vaccine was inoculated by scratches into the superficial layers of the skin, with a wide variety of instruments used to achieve this. They ranged from simple needles to multi-pointed and multi-bladed spring-operated instruments specifically designed for the purpose. A major contribution to smallpox vaccination was made in the 1960s by Benjamin Rubin , an American microbiologist working for Wyeth Laboratories. Based on initial tests with textile needles with the eyes cut off transversely half-way he developed the bifurcated needle . This was a sharpened two-prong fork designed to hold one dose of reconstituted freeze-dried vaccine by capillarity. Easy to use with minimum training, cheap to produce ($5 per 1000), using one quarter as much vaccine as other methods, and repeatedly re-usable after flame sterilization, it was used globally in the WHO Smallpox Eradication Campaign from 1968. : 472–73, 568–72 Rubin estimated that it was used to do 200 million vaccinations per year during the last years of the campaign. Those closely involved in the campaign were awarded the "Order of the Bifurcated Needle". This, a personal initiative by Donald Henderson, was a lapel badge, designed and made by his daughter, formed from the needle shaped to form an "O". This represented "Target Zero", the objective of the campaign. Smallpox was eradicated by a massive international search for outbreaks, backed up with a vaccination program, starting in 1967. It was organised and co-ordinated by a World Health Organization (WHO) unit, set up and headed by Donald Henderson . The last case in the Americas occurred in 1971 (Brazil), south-east Asia (Indonesia) in 1972, and on the Indian subcontinent in 1975 (Bangladesh). After two years of intensive searches, what proved to be the last endemic case anywhere in the world occurred in Somalia, in October 1977. : 526–37 A Global Commission for the Certification of Smallpox Eradication chaired by Frank Fenner examined the evidence from, and visited where necessary, all countries where smallpox had been endemic. In December 1979 they concluded that smallpox had been eradicated; a conclusion endorsed by the WHO General Assembly in May 1980. : 1261–62 However, even as the disease was being eradicated there still remained stocks of smallpox virus in many laboratories. Accelerated by two cases of smallpox in 1978, one fatal ( Janet Parker ), caused by an accidental and unexplained containment breach at a laboratory at the University of Birmingham Medical School , the WHO ensured that known stocks of smallpox virus were either destroyed or moved to safer laboratories. By 1979, only four laboratories were known to have smallpox virus. All English stocks held at St Mary's Hospital, London were transferred to more secure facilities at Porton Down and then to the U.S. at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in 1982, and all South African stocks were destroyed in 1983. By 1984, the only known stocks were kept at the CDC in the U.S. and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia . : 1273–76 These states report that their repositories are for possible anti- bioweaponry research and insurance if some obscure reservoir of natural smallpox is discovered in the future. [ citation needed ] Among more than 270,000 US military service members vaccinated with smallpox vaccine between December 2002, and March 2003, eighteen cases of probable myopericarditis were reported (all in first-time vaccinees who received the NYCBOH strain of vaccinia virus), an incidence of 7.8 per 100,000 during the 30 days they were observed. All cases were in young, otherwise healthy adult white men and all survived. In 2002, the United States government started a program to vaccinate 500,000 volunteer health care professionals throughout the country. Recipients were healthcare workers who would be first-line responders in the event of a bioterrorist attack. Many healthcare workers refused or did not pursue vaccination, worried about vaccine side effects, compensation and liability. Most did not see an immediate need for the vaccine. Some healthcare systems refused to participate, worried about becoming a destination for smallpox patients in the event of an epidemic. Fewer than 40,000 actually received the vaccine. On 21 April 2022, Public Services and Procurement Canada published a notice of tender seeking to stockpile 500,000 doses of smallpox vaccine in order to protect against a potential accidental or intentional release of the eradicated virus. On 6 May, the contract was awarded to Bavarian Nordic for their Imvamune vaccine. These were deployed by the Public Health Agency of Canada for targeted vaccination in response to the 2022 monkeypox outbreak . The origin of the modern smallpox vaccine has long been unclear, but horsepox was identified in the 2010s as the most likely ancestor. : 9 Edward Jenner had obtained his vaccine from a cow, so he named the virus vaccinia , after the Latin word for cow. Jenner believed that both cowpox and smallpox were viruses that originated in the horse and passed to the cow, : 52–53 and some doctors followed his reasoning by inoculating their patients directly with horsepox . The situation was further muddied when Louis Pasteur developed techniques for creating vaccines in the laboratory in the late 19th century. As medical researchers subjected viruses to serial passage , inadequate recordkeeping resulted in the creation of laboratory strains with unclear origins. : 4 By the late 19th century, it was unknown whether the vaccine originated from cowpox, horsepox, or an attenuated strain of smallpox. In 1939, Allan Watt Downie showed that the vaccinia virus was serologically distinct from the "spontaneous" cowpox virus. This work established vaccinia and cowpox as two separate viral species. The term vaccinia now refers only to the smallpox vaccine, while cowpox no longer has a Latin name. The development of whole genome sequencing in the 1990s made it possible to compare orthopoxvirus genomes and identify their relationships with each other. The horsepox virus was sequenced in 2006 and found to be most closely related to vaccinia . In a phylogenetic tree of the orthopoxviruses , horsepox forms a clade with vaccinia strains, and cowpox strains form a different clade. Horsepox is extinct in the wild, and the only known sample was collected in 1976. Because the sample was collected at the end of the smallpox eradication campaign, scientists considered the possibility that horsepox is a strain of vaccinia that had escaped into the wild. However, as more smallpox vaccines were sequenced, older vaccines were found to be more similar to horsepox than modern vaccinia strains. A smallpox vaccine manufactured by Mulford in 1902 is 99.7% similar to horsepox, closer than any previously known strain of vaccinia . Modern Brazilian vaccines with a documented introduction date of 1887, made from material collected in an 1866 outbreak of "cowpox" in France, are more similar to horsepox than other strains of vaccinia . Five smallpox vaccines manufactured in the United States in 1859–1873 are most similar to each other and horsepox, as well as the 1902 Mulford vaccine. One of the 1859–1873 vaccines was identified as a novel strain of horsepox, containing a complete gene from the 1976 horsepox sample that has deletions in vaccinia . The word "vaccine" is derived from Variolae vaccinae (i.e. smallpox of the cow), the term devised by Jenner to denote cowpox and used in the long title of his An enquiry into the causes and effects of Variolae vaccinae, known by the name of cow pox . Vaccination , the term which soon replaced cowpox inoculation and vaccine inoculation , was first used in print by Jenner's friend, Richard Dunning in 1800. Initially, the terms vaccine / vaccination referred only to smallpox, but in 1881 Louis Pasteur proposed at the 7th International Congress of Medicine that to honour Jenner the terms be widened to cover the new protective inoculations being introduced. According to some sources the term was first introduced by Jenner's friend Richard Dunning in 1800.

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Suresh Raina

Suresh Raina ( pronunciation ⓘ ; born 27 November 1986 ) is an Indian former international cricketer . He occasionally served as stand-in captain for Indian men's national cricket team as well as in IPL for Chennai Super Kings during the absence of the main captain, MS Dhoni . He played for Uttar Pradesh (UP) in domestic cricket circuit. He is an aggressive left-handed middle-order batsman and an occasional off-spin bowler. He is the second-youngest player ever to captain India. He was the captain of Gujarat Lions in the Indian Premier League (IPL) , and he also served as vice-captain of the Chennai Super Kings . He is the first Indian batsman to hit a century in all three formats of international cricket . During his time with India, he won the 2011 Cricket World Cup and the 2013 ICC Champions Trophy . Raina made history being the first Indian to score a century in the ICC Men's T20 World Cup , which he did with his 101 runs against South Africa at the 2010 Tournament . On 15 August 2020, Raina announced his retirement from all formats of international cricket. He pulled out of the 2020 Indian Premier League due to personal reasons. On 6 September 2022, he announced his retirement from all forms of cricket, including IPL and domestic cricket. Suresh Kumar Raina was born in Muradnagar of Uttar Pradesh on 27 November 1986 into a Kashmiri Pandit family, to parents from Rainawari, Srinagar district of Jammu and Kashmir . Raina lives in the Rajnagar neighborhood of Ghaziabad city. He has an older brother, Dinesh Raina. He studied in a boarding school [ year needed ] . In 2000, Raina decided to play cricket and subsequently moved from his hometown Muradnagar , Ghaziabad district to Lucknow , to attend the Guru Gobind Singh Sports College, Lucknow . He rose to become the captain of the Uttar Pradesh U-16s and came to prominence amongst Indian selectors in 2002 when he was selected at the age of 15 + 1 ⁄ 2 years for the U-19 tour to England, where he made a pair of half-centuries in the U-19 Test matches. He toured Sri Lanka later that year with the U-17 team. He made his Ranji Trophy debut for Uttar Pradesh against Assam in February 2003 at the age of 16 but did not play another match until the following season. He debuted in List A Cricket against Madhya Pradesh at Indore in 2005 and scored 16 runs. He played for India green, UP under 16, India Blue, India Red, Rest of India, India under 19, Indian board's president's XI, Rajasthan Cricket association's president's XI, India seniors, Central zone. In Ranji trophy 2005-06 season he scored 620 in 6 games. In 2018 Akshdeep Nath replaced him as UP's Ranji trophy captain due to poor performance of scoring 105 runs in 9 innings averaging 11.66. In late 2003, he toured Pakistan for the U-19 Asian ODI Championship before being selected for the 2004 U-19 World Cup , where he scored three half-centuries, including a 90 scored off only 38 balls. He was then awarded a Border-Gavaskar scholarship to train at the Australian Cricket Academy and in early 2005, he made his first-class limited overs debut, and scored 645 runs that season at an average of 53.75. Raina was awarded "best fielder" by the BCCI ahead of the finals of IPL 2010 . He played a vital half-century which turned the final to Chennai's tide who ultimately went on to become the champions beating the Mumbai Indians . For his performances in 2010, he was named in the ESPNcricinfo IPL XI. For his performances in 2013, he was named in the ESPNcricinfo CLT20 XI. On 30 May 2014, he made 87 runs out of 25 balls against Kings XI Punjab in qualifier 2. He missed the fastest century of the cricketing history by just 13 runs due to a runout. For his performances in 2014, he was named in the ESPNcricinfo IPL XI and ESPNcricinfo CLT20 XI. In 2016 , Raina was signed for the Gujarat Lions after the suspension of CSK . He captained the team for the season, and remained consistent with batting, scoring 399 runs in 15 innings. Raina had to leave for the Netherlands in between of season 9 for birth of his first child thus making him miss his first ever match in nine seasons of IPL. On the occasion of the 10 year anniversary of IPL, he was also named in the all-time ESPNcricinfo IPL XI. He was named in the Cricbuzz IPL XI of the tournament for 2017. In IPL 2018 , Raina was retained by the returning Super Kings for a price tag of 11 crore ($1.7 million). During the second game of the tournament, Raina suffered a calf injury, due to which he was ruled out of the next two games. On 23 March 2019, in the first match of the 12th edition of the tournament against RCB , he became the first batsman to score 5000 runs in the IPL. In 2020, Raina flew to UAE where the IPL was to be played due to the ongoing COVID-19 pandemic with the Super Kings squad but days later returned to India and withdrew from the 2020 season of IPL citing personal reasons. In 2021, Raina became the fourth player in IPL history to play 200 matches, behind MS Dhoni , Rohit Sharma and Dinesh Karthik . He went unsold in the 2022 IPL Auctions . He then became a commentator for the tournament. In September 2022 he signed a contract with the Road Safety World Series league and played for 'Indian Legends' team. In 2023, he was selected as the captain by Urbanrisers Hyderabad in Legends League Cricket and the team made it to the finals . Raina was awarded "best fielder" by the BCCI ahead of the finals of IPL 2010 . He played a vital half-century which turned the final to Chennai's tide who ultimately went on to become the champions beating the Mumbai Indians . For his performances in 2010, he was named in the ESPNcricinfo IPL XI. For his performances in 2013, he was named in the ESPNcricinfo CLT20 XI. On 30 May 2014, he made 87 runs out of 25 balls against Kings XI Punjab in qualifier 2. He missed the fastest century of the cricketing history by just 13 runs due to a runout. For his performances in 2014, he was named in the ESPNcricinfo IPL XI and ESPNcricinfo CLT20 XI. In 2016 , Raina was signed for the Gujarat Lions after the suspension of CSK . He captained the team for the season, and remained consistent with batting, scoring 399 runs in 15 innings. Raina had to leave for the Netherlands in between of season 9 for birth of his first child thus making him miss his first ever match in nine seasons of IPL. On the occasion of the 10 year anniversary of IPL, he was also named in the all-time ESPNcricinfo IPL XI. He was named in the Cricbuzz IPL XI of the tournament for 2017. In IPL 2018 , Raina was retained by the returning Super Kings for a price tag of 11 crore ($1.7 million). During the second game of the tournament, Raina suffered a calf injury, due to which he was ruled out of the next two games. On 23 March 2019, in the first match of the 12th edition of the tournament against RCB , he became the first batsman to score 5000 runs in the IPL. In 2020, Raina flew to UAE where the IPL was to be played due to the ongoing COVID-19 pandemic with the Super Kings squad but days later returned to India and withdrew from the 2020 season of IPL citing personal reasons. In 2021, Raina became the fourth player in IPL history to play 200 matches, behind MS Dhoni , Rohit Sharma and Dinesh Karthik . He went unsold in the 2022 IPL Auctions . He then became a commentator for the tournament. In September 2022 he signed a contract with the Road Safety World Series league and played for 'Indian Legends' team. In 2023, he was selected as the captain by Urbanrisers Hyderabad in Legends League Cricket and the team made it to the finals . Raina was one of the few best fielders during his time with Indian team. He played in middle order. During the semi-final of 2011 Cricket World Cup , Raina batted with tailenders to score an unbeaten 36, a significant contribution to India's final tally of 260. Apart from a half-century in the first Test of India tour of England 2011 at Lord's, Raina managed just 27 runs from seven innings. He struggled against short bowling and in the final Test was out for a 29-ball duck, the longest in India's Test history. In the second ODI of Indian tour of Sri Lanka 2012 , he was out for 1 but he came back stronger in the third ODI where he played 45 balls 65 to hand India a five-wicket win and he eventually also won the man of the match award for his performance. After the Tour of Sri Lanka, when the England team came to India, he was dropped and his spot was given to Yuvraj Singh, who made a comeback after suffering from cancer. He was named as 12th man in the 'Team of the Tournament' for the 2012 T20 World Cup by the ICC. His knock of 100 against England during England tour of India 2012–13 at Cardiff was nominated to be one of the best ODI batting performance of the year by ESPNcricinfo. Raina was not selected in India's first tour to USA , where they played against West Indies for 2 T20Is. However, he made a re-entry to the ODI team for a series against New Zealand . Later he was ruled out due to Chikungunya . In 2011, India toured West Indies after the World Cup with captain MS Dhoni rested and vice-captain Virender Sehwag injured. Gautam Gambhir was named the captain for the ODIs and T20's with Raina as his deputy. But due to injury, Gautam Gambhir was ruled out with Raina captaining with Harbhajan Singh as his deputy. During the 2014 Bangladesh series, he led his team to a 2–0 victory in the series. During the 2nd match of the series, India was all out for 105 runs while batting first. Suresh Raina and his team successfully defended the total of 105 runs, winning the match by 47 runs. Raina returned to the Indian T20 international side in February 2018 on the back of his recent performance in domestic cricket particularly Syed Mushtaq Ali Trophy . He was named in the Indian T20I squad where India would face South Africa in three match T20I series. The series went well for him as he became the talk of the town as he smashed 43 runs off 27 balls to help India post a competitive total on board in the final T20I. Not just that, he also chipped in with the ball, returning with figures of 1/27 off his 3 overs and was rewarded with the Man of the Match award. In October 2018, he was named in India C's squad for the 2018–19 Deodhar Trophy. Raina announced his retirement from all formats of international cricket on 15 August 2020, minutes after the retirement of Mahendra Singh Dhoni . On Instagram, Raina said "It was nothing but lovely playing with you, @mahi7781. With my heart full of pride, I choose to join you in your journey. Thank you India. Jai Hind." Raina is an attacking middle order left handed batter. He had more success in limited over cricket than in test. He has weakness of short pitched balls and throughout his career opposition teams tried to exploit this weakness. Also in Ranji trophy he has struggled against short balls. He has been widely criticised for his short ball weakness. He is part time off break bowler. His favourite scoring area is mid wickets on side. Most of the times he plays inside out off drive shot . While trying to hit on off side , he creates room for himself. He is particularly strong on the leg side, where he employs a wide array of shots, including the flick, pull, and slog sweep. In addition to his batting skills, Raina is an exceptional fielder, renowned for his agility, sharp reflexes, and throwing accuracy. He is often stationed in the inner ring, saving runs and effecting crucial run-outs. Former South African Cricketer Jonty Rhodes has ranked Suresh Raina as Number 1 in his 'top fielders' list Suresh Raina's father Trilokchand Raina was a military officer in an ordinance factory. His family left 'Rainawari' in Jammu and Kashmir union territory of India amid the exodus of Kashmiri Hindus in the 1990s and settled down in Muradnagar town , Ghaziabad district , Uttar Pradesh . Raina trained in the Guru Gobind Singh sports college, Lucknow in 1998. Raina has a sister and his one elder brother is in Indian Army . Raina married Priyanka on 3 April 2015. They have two children. Raina's uncle Ashok Kumar was assaulted during a robbery in their house in Punjab , and didn't survive. Due to this, Raina withdrew from 2020 IPL season to be with his family. Raina received an honorary doctorate from Vels University on 5 August 2022. 12 July 2023 is the Grand Opening of his Indian restaurant in Amsterdam , where he will be serving authentic Indian cuisine.

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Herpes

Herpes simplex , often known simply as herpes , is a viral infection caused by the herpes simplex virus . Herpes infections are categorized by the area of the body that is infected. The two major types of herpes are oral herpes and genital herpes , though other forms also exist. Oral herpes involves the face or mouth. It may result in small blisters in groups, often called cold sores or fever blisters, or may just cause a sore throat. Genital herpes involves the genitalia . It may have minimal symptoms or form blisters that break open and result in small ulcers . These typically heal over two to four weeks. Tingling or shooting pains may occur before the blisters appear. Herpes cycles between periods of active disease followed by periods without symptoms. The first episode is often more severe and may be associated with fever, muscle pains, swollen lymph nodes and headaches. Over time, episodes of active disease decrease in frequency and severity. Herpetic whitlow typically involves the fingers or thumb, herpes simplex keratitis involves the eye, herpesviral encephalitis involves the brain, and neonatal herpes involves any part of the body of a newborn, among others. There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2). HSV-1 more commonly causes infections around the mouth while HSV-2 more commonly causes genital infections. They are transmitted by direct contact with body fluids or lesions of an infected individual. Transmission may still occur when symptoms are not present. Genital herpes is classified as a sexually transmitted infection . It may be spread to an infant during childbirth. After infection, the viruses are transported along sensory nerves to the nerve cell bodies, where they reside lifelong . Causes of recurrence may include: decreased immune function , stress, and sunlight exposure. Oral and genital herpes is usually diagnosed based on the presenting symptoms. The diagnosis may be confirmed by viral culture or detecting herpes DNA in fluid from blisters. Testing the blood for antibodies against the virus can confirm a previous infection but will be negative in new infections. The most effective method of avoiding genital infections is by avoiding vaginal, oral, manual, and anal sex. Condom use decreases the risk. Daily antiviral medication taken by someone who has the infection can also reduce spread. There is no available vaccine and once infected, there is no cure. Paracetamol (acetaminophen) and topical lidocaine may be used to help with the symptoms. Treatments with antiviral medication such as aciclovir or valaciclovir can lessen the severity of symptomatic episodes. Worldwide rates of either HSV-1 or HSV-2 are between 60% and 95% in adults. HSV-1 is usually acquired during childhood. Since there is no cure for either HSV-1 or HSV-2, rates of both inherently increase as people age. Rates of HSV-1 are between 70% and 80% in populations of low socioeconomic status and 40% to 60% in populations of improved socioeconomic status. An estimated 536 million people worldwide (16% of the population) were infected with HSV-2 as of 2003 with greater rates among women and those in the developing world. Most people with HSV-2 do not realize that they are infected. The name is from Greek : ἕρπης herpēs , which is related to the meaning "to creep", referring to spreading blisters. The name does not refer to latency. HSV infection causes several distinct medical disorders . Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands ( herpetic whitlow ). More serious disorders occur when the virus infects and damages the eye ( herpes keratitis ), or invades the central nervous system, damaging the brain (herpes encephalitis). People with immature or suppressed immune systems, such as newborns, transplant recipients, or people with AIDS, are prone to severe complications from HSV infections. HSV infection has also been associated with cognitive deficits of bipolar disorder , and Alzheimer's disease , although this is often dependent on the genetics of the infected person. In all cases, HSV is never removed from the body by the immune system . Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion . As a result of primary infection, the body produces antibodies to the particular type of HSV involved, which can help reduce the odds of subsequent infection of that type at a different site. In HSV-1-infected individuals, seroconversion after an oral infection helps prevent additional HSV-1 infections such as whitlow, genital herpes, and herpes of the eye. Prior HSV-1 seroconversion seems to reduce the symptoms of a later HSV-2 infection, although HSV-2 can still be contracted. Many people infected with HSV-2 display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having subclinical herpes. However, infection with herpes can be fatal. Neonatal herpes simplex is an HSV infection in an infant. It is a rare but serious condition, usually caused by vertical transmission of HSV-1 or -2 from mother to newborn. During immunodeficiency, herpes simplex can cause unusual lesions in the skin. One of the most striking is the appearance of clean linear erosions in skin creases, with the appearance of a knife cut. Herpetic sycosis is a recurrent or initial herpes simplex infection affecting primarily the hair follicles. : 369 Eczema herpeticum is an infection with herpesvirus in patients with chronic atopic dermatitis may result in spread of herpes simplex throughout the eczematous areas. : 373 Herpetic keratoconjunctivitis , a primary infection, typically presents as swelling of the conjunctiva and eyelids ( blepharoconjunctivitis ), accompanied by small white itchy lesions on the surface of the cornea . Herpetic sycosis is a recurrent or initial herpes simplex infection affecting primarily the hair follicle . : 369 Although the exact cause of Bell's palsy — a type of facial paralysis — is unknown, it may be related to the reactivation of HSV-1. This theory has been contested, however, since HSV is detected in large numbers of individuals having never experienced facial paralysis, and higher levels of antibodies for HSV are not found in HSV-infected individuals with Bell's palsy compared to those without. Antivirals may improve the condition slightly when used together with corticosteroids in those with severe disease. HSV-1 has been proposed as a possible cause of Alzheimer's disease . In the presence of a certain gene variation ( APOE -epsilon4 allele carriers), HSV-1 appears to be particularly damaging to the nervous system and increases one's risk of developing Alzheimer's disease. The virus interacts with the components and receptors of lipoproteins , which may lead to its development. Neonatal herpes simplex is an HSV infection in an infant. It is a rare but serious condition, usually caused by vertical transmission of HSV-1 or -2 from mother to newborn. During immunodeficiency, herpes simplex can cause unusual lesions in the skin. One of the most striking is the appearance of clean linear erosions in skin creases, with the appearance of a knife cut. Herpetic sycosis is a recurrent or initial herpes simplex infection affecting primarily the hair follicles. : 369 Eczema herpeticum is an infection with herpesvirus in patients with chronic atopic dermatitis may result in spread of herpes simplex throughout the eczematous areas. : 373 Herpetic keratoconjunctivitis , a primary infection, typically presents as swelling of the conjunctiva and eyelids ( blepharoconjunctivitis ), accompanied by small white itchy lesions on the surface of the cornea . Herpetic sycosis is a recurrent or initial herpes simplex infection affecting primarily the hair follicle . : 369 Although the exact cause of Bell's palsy — a type of facial paralysis — is unknown, it may be related to the reactivation of HSV-1. This theory has been contested, however, since HSV is detected in large numbers of individuals having never experienced facial paralysis, and higher levels of antibodies for HSV are not found in HSV-infected individuals with Bell's palsy compared to those without. Antivirals may improve the condition slightly when used together with corticosteroids in those with severe disease. HSV-1 has been proposed as a possible cause of Alzheimer's disease . In the presence of a certain gene variation ( APOE -epsilon4 allele carriers), HSV-1 appears to be particularly damaging to the nervous system and increases one's risk of developing Alzheimer's disease. The virus interacts with the components and receptors of lipoproteins , which may lead to its development. Herpes is contracted through direct contact with an active lesion or body fluid of an infected person. Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person. Herpes simplex virus 2 is typically contracted through direct skin-to-skin contact with an infected individual, but can also be contracted by exposure to infected saliva, semen, vaginal fluid, or the fluid from herpetic blisters. To infect a new individual, HSV travels through tiny breaks in the skin or mucous membranes in the mouth or genital areas. Even microscopic abrasions on mucous membranes are sufficient to allow viral entry. HSV asymptomatic shedding occurs at some time in most individuals infected with herpes. It can occur more than a week before or after a symptomatic recurrence in 50% of cases. Virus enters into susceptible cells by entry receptors such as nectin-1, HVEM and 3-O sulfated heparan sulfate. Infected people who show no visible symptoms may still shed and transmit viruses through their skin; asymptomatic shedding may represent the most common form of HSV-2 transmission. Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV. Concurrent infection with HIV increases the frequency and duration of asymptomatic shedding. Some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified; no significant differences are seen in the frequency of asymptomatic shedding when comparing persons with one to 12 annual recurrences to those with no recurrences. Antibodies that develop following an initial infection with a type of HSV can reduce the odds of reinfection with the same virus type. In a monogamous couple, a seronegative female runs a greater than 30% per year risk of contracting an HSV infection from a seropositive male partner. If an oral HSV-1 infection is contracted first, seroconversion will have occurred after 6 weeks to provide protective antibodies against a future genital HSV-1 infection. Herpes simplex is a double-stranded DNA virus . Herpes simplex virus is divided into two types. However, each may cause infections in all areas. Primary orofacial herpes is readily identified by examination of persons with no previous history of lesions and contact with an individual with known HSV infection. The appearance and distribution of sores is typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis . Adults with atypical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis . When lesions do not appear inside the mouth, primary orofacial herpes is sometimes mistaken for impetigo , a bacterial infection . Common mouth ulcers ( aphthous ulcer ) also resemble intraoral herpes, but do not present a vesicular stage. Genital herpes can be more difficult to diagnose than oral herpes, since most people have none of the classical symptoms. Further confusing diagnosis, several other conditions resemble genital herpes, including fungal infection , lichen planus , atopic dermatitis , and urethritis . Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy , and polymerase chain reaction to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice. Until the 1980s serological tests for antibodies to HSV were rarely useful to diagnosis and not routinely used in clinical practice. The older IgM serologic assay could not differentiate between antibodies generated in response to HSV-1 or HSV-2 infection. However, a glycoprotein G-specific (IgG) HSV test introduced in the 1980s is more than 98% specific at discriminating HSV-1 from HSV-2. It should not be confused with conditions caused by other viruses in the herpesviridae family such as herpes zoster (also known as shingles), which is caused by varicella zoster virus . The differential diagnosis includes hand, foot and mouth disease due to similar lesions on the skin. Lymphangioma circumscriptum and dermatitis herpetiformis may also have a similar appearance.Herpes simplex virus is divided into two types. However, each may cause infections in all areas. Primary orofacial herpes is readily identified by examination of persons with no previous history of lesions and contact with an individual with known HSV infection. The appearance and distribution of sores is typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis . Adults with atypical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis . When lesions do not appear inside the mouth, primary orofacial herpes is sometimes mistaken for impetigo , a bacterial infection . Common mouth ulcers ( aphthous ulcer ) also resemble intraoral herpes, but do not present a vesicular stage. Genital herpes can be more difficult to diagnose than oral herpes, since most people have none of the classical symptoms. Further confusing diagnosis, several other conditions resemble genital herpes, including fungal infection , lichen planus , atopic dermatitis , and urethritis . Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy , and polymerase chain reaction to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice. Until the 1980s serological tests for antibodies to HSV were rarely useful to diagnosis and not routinely used in clinical practice. The older IgM serologic assay could not differentiate between antibodies generated in response to HSV-1 or HSV-2 infection. However, a glycoprotein G-specific (IgG) HSV test introduced in the 1980s is more than 98% specific at discriminating HSV-1 from HSV-2. It should not be confused with conditions caused by other viruses in the herpesviridae family such as herpes zoster (also known as shingles), which is caused by varicella zoster virus . The differential diagnosis includes hand, foot and mouth disease due to similar lesions on the skin. Lymphangioma circumscriptum and dermatitis herpetiformis may also have a similar appearance.As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men. On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is about 8–11%. This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Transmission risk from infected female to male is around 4–5% annually. Suppressive antiviral therapy reduces these risks by 50%. Antivirals also help prevent the development of symptomatic HSV in infection scenarios, meaning the infected partner will be seropositive but symptom-free by about 50%. Condom use also reduces the transmission risk significantly. Condom use is much more effective at preventing male-to-female transmission than vice versa . Previous HSV-1 infection may reduce the risk for acquisition of HSV-2 infection among women by a factor of three, although the one study that states this has a small sample size of 14 transmissions out of 214 couples. However, asymptomatic carriers of the HSV-2 virus are still contagious. In many infections, the first symptom people will have of their own infections is the horizontal transmission to a sexual partner or the vertical transmission of neonatal herpes to a newborn at term. Since most asymptomatic individuals are unaware of their infection, they are considered at high risk for spreading HSV. In October 2011, the anti-HIV drug tenofovir , when used topically in a microbicidal vaginal gel, was reported to reduce herpes virus sexual transmission by 51%. Condoms offer moderate protection against HSV-2 in both men and women, with consistent condom users having a 30%-lower risk of HSV-2 acquisition compared with those who never use condoms. A female condom can provide greater protection than the male condom, as it covers the labia. The virus cannot pass through a synthetic condom, but a male condom's effectiveness is limited because herpes ulcers may appear on areas not covered by it. Neither type of condom prevents contact with the scrotum, anus, buttocks, or upper thighs, areas that may come in contact with ulcers or genital secretions during sexual activity. Protection against herpes simplex depends on the site of the ulcer; therefore, if ulcers appear on areas not covered by condoms, abstaining from sexual activity until the ulcers are fully healed is one way to limit risk of transmission. The risk is not eliminated, however, as viral shedding capable of transmitting infection may still occur while the infected partner is asymptomatic. The use of condoms or dental dams also limits the transmission of herpes from the genitals of one partner to the mouth of the other (or vice versa ) during oral sex . When one partner has a herpes simplex infection and the other does not, the use of antiviral medication, such as valaciclovir , in conjunction with a condom, further decreases the chances of transmission to the uninfected partner. Topical microbicides that contain chemicals that directly inactivate the virus and block viral entry are being investigated. Antivirals may reduce asymptomatic shedding; asymptomatic genital HSV-2 viral shedding is believed to occur on 20% of days per year in patients not undergoing antiviral treatment, versus 10% of days while on antiviral therapy. The risk of transmission from mother to baby is highest if the mother becomes infected around the time of delivery (30% to 60%), since insufficient time will have occurred for the generation and transfer of protective maternal antibodies before the birth of the child. In contrast, the risk falls to 3% if the infection is recurrent, and is 1–3% if the woman is seropositive for both HSV-1 and HSV-2, and is less than 1% if no lesions are visible. Women seropositive for only one type of HSV are only half as likely to transmit HSV as infected seronegative mothers. To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1-seropositive partner and conventional sex with a partner having a genital infection during the last trimester of pregnancy. Mothers infected with HSV are advised to avoid procedures that would cause trauma to the infant during birth (e.g. fetal scalp electrodes, forceps, and vacuum extractors) and, should lesions be present, to elect caesarean section to reduce exposure of the child to infected secretions in the birth canal. The use of antiviral treatments, such as aciclovir, given from the 36th week of pregnancy, limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section. Aciclovir is the recommended antiviral for herpes suppressive therapy during the last months of pregnancy. The use of valaciclovir and famciclovir, while potentially improving compliance, have less-well-determined safety in pregnancy.Condoms offer moderate protection against HSV-2 in both men and women, with consistent condom users having a 30%-lower risk of HSV-2 acquisition compared with those who never use condoms. A female condom can provide greater protection than the male condom, as it covers the labia. The virus cannot pass through a synthetic condom, but a male condom's effectiveness is limited because herpes ulcers may appear on areas not covered by it. Neither type of condom prevents contact with the scrotum, anus, buttocks, or upper thighs, areas that may come in contact with ulcers or genital secretions during sexual activity. Protection against herpes simplex depends on the site of the ulcer; therefore, if ulcers appear on areas not covered by condoms, abstaining from sexual activity until the ulcers are fully healed is one way to limit risk of transmission. The risk is not eliminated, however, as viral shedding capable of transmitting infection may still occur while the infected partner is asymptomatic. The use of condoms or dental dams also limits the transmission of herpes from the genitals of one partner to the mouth of the other (or vice versa ) during oral sex . When one partner has a herpes simplex infection and the other does not, the use of antiviral medication, such as valaciclovir , in conjunction with a condom, further decreases the chances of transmission to the uninfected partner. Topical microbicides that contain chemicals that directly inactivate the virus and block viral entry are being investigated. Antivirals may reduce asymptomatic shedding; asymptomatic genital HSV-2 viral shedding is believed to occur on 20% of days per year in patients not undergoing antiviral treatment, versus 10% of days while on antiviral therapy. The risk of transmission from mother to baby is highest if the mother becomes infected around the time of delivery (30% to 60%), since insufficient time will have occurred for the generation and transfer of protective maternal antibodies before the birth of the child. In contrast, the risk falls to 3% if the infection is recurrent, and is 1–3% if the woman is seropositive for both HSV-1 and HSV-2, and is less than 1% if no lesions are visible. Women seropositive for only one type of HSV are only half as likely to transmit HSV as infected seronegative mothers. To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1-seropositive partner and conventional sex with a partner having a genital infection during the last trimester of pregnancy. Mothers infected with HSV are advised to avoid procedures that would cause trauma to the infant during birth (e.g. fetal scalp electrodes, forceps, and vacuum extractors) and, should lesions be present, to elect caesarean section to reduce exposure of the child to infected secretions in the birth canal. The use of antiviral treatments, such as aciclovir, given from the 36th week of pregnancy, limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section. Aciclovir is the recommended antiviral for herpes suppressive therapy during the last months of pregnancy. The use of valaciclovir and famciclovir, while potentially improving compliance, have less-well-determined safety in pregnancy.No method eradicates herpes virus from the body, but antiviral medications can reduce the frequency, duration, and severity of outbreaks. Analgesics such as ibuprofen and paracetamol (acetaminophen) can reduce pain and fever. Topical anesthetic treatments such as prilocaine , lidocaine , benzocaine , or tetracaine can also relieve itching and pain. Several antiviral drugs are effective for treating herpes, including aciclovir (acyclovir), valaciclovir , famciclovir , and penciclovir . Aciclovir was the first discovered and is now available in generic . Valaciclovir is also available as a generic and is slightly more effective than aciclovir for reducing lesion healing time. Evidence supports the use of aciclovir and valaciclovir in the treatment of herpes labialis as well as herpes infections in people with cancer . The evidence to support the use of aciclovir in primary herpetic gingivostomatitis is weaker. A number of topical antivirals are effective for herpes labialis, including aciclovir, penciclovir, and docosanol . Evidence is insufficient to support use of many of these compounds, including echinacea , eleuthero , L-lysine , zinc , monolaurin bee products, and aloe vera . While a number of small studies show possible benefit from monolaurin, L-lysine, aspirin , lemon balm, topical zinc, or licorice root cream in treatment, these preliminary studies have not been confirmed by higher-quality randomized controlled studies . Several antiviral drugs are effective for treating herpes, including aciclovir (acyclovir), valaciclovir , famciclovir , and penciclovir . Aciclovir was the first discovered and is now available in generic . Valaciclovir is also available as a generic and is slightly more effective than aciclovir for reducing lesion healing time. Evidence supports the use of aciclovir and valaciclovir in the treatment of herpes labialis as well as herpes infections in people with cancer . The evidence to support the use of aciclovir in primary herpetic gingivostomatitis is weaker. A number of topical antivirals are effective for herpes labialis, including aciclovir, penciclovir, and docosanol . Evidence is insufficient to support use of many of these compounds, including echinacea , eleuthero , L-lysine , zinc , monolaurin bee products, and aloe vera . While a number of small studies show possible benefit from monolaurin, L-lysine, aspirin , lemon balm, topical zinc, or licorice root cream in treatment, these preliminary studies have not been confirmed by higher-quality randomized controlled studies . Following active infection, herpes viruses establish a latent infection in sensory and autonomic ganglia of the nervous system. The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the nucleus of a nerve's cell body . HSV latency is static; no virus is produced; and is controlled by a number of viral genes, including latency-associated transcript . Many HSV-infected people experience recurrence within the first year of infection. Prodrome precedes development of lesions. Prodromal symptoms include tingling ( paresthesia ), itching, and pain where lumbosacral nerves innervate the skin. Prodrome may occur as long as several days or as short as a few hours before lesions develop. Beginning antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions in some individuals. During recurrence, fewer lesions are likely to develop and are less painful and heal faster (within 5–10 days without antiviral treatment) than those occurring during the primary infection. Subsequent outbreaks tend to be periodic or episodic, occurring on average four or five times a year when not using antiviral therapy. The causes of reactivation are uncertain, but several potential triggers have been documented. A 2009 study showed the protein VP16 plays a key role in reactivation of the dormant virus. Changes in the immune system during menstruation may play a role in HSV-1 reactivation. Concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks. Reactivation due to other infections is the likely source of the historic terms 'cold sore' and 'fever blister'. Other identified triggers include local injury to the face, lips, eyes, or mouth; trauma; surgery; radiotherapy ; and exposure to wind, ultraviolet light , or sunlight. The frequency and severity of recurrent outbreaks vary greatly between people. Some individuals' outbreaks can be quite debilitating, with large, painful lesions persisting for several weeks, while others experience only minor itching or burning for a few days. Some evidence indicates genetics play a role in the frequency of cold sore outbreaks. An area of human chromosome 21 that includes six genes has been linked to frequent oral herpes outbreaks. An immunity to the virus is built over time. Most infected individuals experience fewer outbreaks and outbreak symptoms often become less severe. After several years, some people become perpetually asymptomatic and no longer experience outbreaks, though they may still be contagious to others. Immunocompromised individuals may experience longer, more frequent, and more severe episodes. Antiviral medication has been proven to shorten the frequency and duration of outbreaks. Outbreaks may occur at the original site of the infection or in proximity to nerve endings that reach out from the infected ganglia. In the case of a genital infection, sores can appear at the original site of infection or near the base of the spine, the buttocks, or the back of the thighs. HSV-2-infected individuals are at higher risk for acquiring HIV when practicing unprotected sex with HIV-positive persons, in particular during an outbreak with active lesions. Worldwide rates of either HSV-1 and/or HSV-2 are between 60 and 95% in adults. HSV-1 is more common than HSV-2, with rates of both increasing as people age. HSV-1 rates are between 70% and 80% in populations of low socioeconomic status and 40% to 60% in populations of improved socioeconomic status. An estimated 536 million people or 16% of the population worldwide were infected with HSV-2 as of 2003 with greater rates among women and in those in the developing world. Rates of infection are determined by the presence of antibodies against either viral species . In the US , 58% of the population is infected with HSV-1 and 16% are infected with HSV-2. Among those HSV-2-seropositive, only 19% were aware they were infected. During 2005–2008, the prevalence of HSV-2 was 39% in black people and 21% in women. The annual incidence in Canada of genital herpes due to HSV-1 and HSV-2 infection is not known (for a review of HSV-1/HSV-2 prevalence and incidence studies worldwide, see Smith and Robinson 2002). As many as one in seven Canadians aged 14 to 59 may be infected with herpes simplex type 2 virus and more than 90 per cent of them may be unaware of their status, a new study suggests. In the United States, it is estimated that about 1,640,000 HSV-2 seroconversions occur yearly (730,000 men and 910,000 women, or 8.4 per 1,000 persons). In British Columbia in 1999, the seroprevalence of HSV-2 antibody in leftover serum submitted for antenatal testing revealed a prevalence of 17%, ranging from 7% in women 15–19 years old to 28% in those 40–44 years. In Norway, a study published in 2000 found that up to 70–90% of genital initial infections were due to HSV-1. In Nova Scotia, 58% of 1,790 HSV isolates from genital lesion cultures in women were HSV-1; in men, 37% of 468 isolates were HSV-1. Herpes has been known for at least 2,000 years. Emperor Tiberius is said to have banned kissing in Rome for a time due to so many people having cold sores. In the 16th century Romeo and Juliet , blisters "o'er ladies' lips" are mentioned. In the 18th century, it was so common among prostitutes that it was called "a vocational disease of women". The term 'herpes simplex' appeared in Richard Boulton 's A System of Rational and Practical Chirurgery in 1713, where the terms 'herpes miliaris' and 'herpes exedens' also appeared. Herpes was not found to be a virus until the 1940s. Herpes antiviral therapy began in the early 1960s with the experimental use of medications that interfered with viral replication called deoxyribonucleic acid (DNA) inhibitors. The original use was against normally fatal or debilitating illnesses such as adult encephalitis, keratitis, in immunocompromised (transplant) patients, or disseminated herpes zoster (also known as disseminated shingles). The original compounds used were 5-iodo-2'-deoxyuridine, AKA idoxuridine, IUdR, or(IDU) and 1-β-D-arabinofuranosylcytosine or ara-C, later marketed under the name cytosar or cytarabine. The usage expanded to include topical treatment of herpes simplex, zoster, and varicella. Some trials combined different antivirals with differing results. The introduction of 9-β-D-arabinofuranosyladenine, (ara-A or vidarabine), considerably less toxic than ara-C, in the mid-1970s, heralded the way for the beginning of regular neonatal antiviral treatment. Vidarabine was the first systemically administered antiviral medication with activity against HSV for which therapeutic efficacy outweighed toxicity for the management of life-threatening HSV disease. Intravenous vidarabine was licensed for use by the U.S. Food and Drug Administration in 1977. Other experimental antivirals of that period included: heparin, trifluorothymidine (TFT), Ribivarin, interferon, Virazole, and 5-methoxymethyl-2'-deoxyuridine (MMUdR). The introduction of 9-(2-hydroxyethoxymethyl)guanine, AKA aciclovir, in the late 1970s raised antiviral treatment another notch and led to vidarabine vs. aciclovir trials in the late 1980s. The lower toxicity and ease of administration over vidarabine has led to aciclovir becoming the drug of choice for herpes treatment after it was licensed by the FDA in 1998. Another advantage in the treatment of neonatal herpes included greater reductions in mortality and morbidity with increased dosages, which did not occur when compared with increased dosages of vidarabine. However, aciclovir seems to inhibit antibody response, and newborns on aciclovir antiviral treatment experienced a slower rise in antibody titer than those on vidarabine. Some people experience negative feelings related to the condition following diagnosis, in particular, if they have acquired the genital form of the disease. Feelings can include depression , fear of rejection, feelings of isolation , fear of being found out, and self-destructive feelings. Herpes support groups have been formed in the United States and the United Kingdom, providing information about herpes and running message forums and dating websites for affected people. People with the herpes virus are often hesitant to divulge to other people, including friends and family, that they are infected. This is especially true of new or potential sexual partners whom they consider casual. In a 2007 study, 1,900 people (25% of which had herpes) ranked genital herpes second for social stigma, out of all sexually transmitted diseases ( HIV took the top spot for STD stigma). A source of support is the National Herpes Resource Center which arose from the work of the American Sexual Health Association (ASHA). The ASHA was created in 1914 in response to the increase in sexually transmitted diseases that had spread during World War I . During the 1970s, there was an increase in sexually transmitted diseases. One of the diseases that increased dramatically was genital herpes. In response, ASHA created the National Herpes Resource Center in 1979. The Herpes Resource Center (HRC) was designed to meet the growing need for education and awareness about the virus. One of the projects of the HRC was to create a network of local support (HELP) groups. The goal of these HELP groups was to provide a safe, confidential environment where participants can get accurate information and share experiences, fears, and feelings with others who are concerned about herpes. In the UK, the Herpes Association (now the Herpes Viruses Association ) was started in 1982, becoming a registered charity with a Department of Health grant in 1985. The charity started as a string of local group meetings before acquiring an office and a national spread. A source of support is the National Herpes Resource Center which arose from the work of the American Sexual Health Association (ASHA). The ASHA was created in 1914 in response to the increase in sexually transmitted diseases that had spread during World War I . During the 1970s, there was an increase in sexually transmitted diseases. One of the diseases that increased dramatically was genital herpes. In response, ASHA created the National Herpes Resource Center in 1979. The Herpes Resource Center (HRC) was designed to meet the growing need for education and awareness about the virus. One of the projects of the HRC was to create a network of local support (HELP) groups. The goal of these HELP groups was to provide a safe, confidential environment where participants can get accurate information and share experiences, fears, and feelings with others who are concerned about herpes. In the UK, the Herpes Association (now the Herpes Viruses Association ) was started in 1982, becoming a registered charity with a Department of Health grant in 1985. The charity started as a string of local group meetings before acquiring an office and a national spread. A source of support is the National Herpes Resource Center which arose from the work of the American Sexual Health Association (ASHA). The ASHA was created in 1914 in response to the increase in sexually transmitted diseases that had spread during World War I . During the 1970s, there was an increase in sexually transmitted diseases. One of the diseases that increased dramatically was genital herpes. In response, ASHA created the National Herpes Resource Center in 1979. The Herpes Resource Center (HRC) was designed to meet the growing need for education and awareness about the virus. One of the projects of the HRC was to create a network of local support (HELP) groups. The goal of these HELP groups was to provide a safe, confidential environment where participants can get accurate information and share experiences, fears, and feelings with others who are concerned about herpes. In the UK, the Herpes Association (now the Herpes Viruses Association ) was started in 1982, becoming a registered charity with a Department of Health grant in 1985. The charity started as a string of local group meetings before acquiring an office and a national spread. Research has gone into vaccines for both prevention and treatment of herpes infections. As of October 2022, the U.S. FDA have not approved a vaccine for herpes. However, there are herpes vaccines currently in clinical trials, such as Moderna mRNA-1608. Unsuccessful clinical trials have been conducted for some glycoprotein subunit vaccines. [ citation needed ] As of 2017, the future pipeline includes several promising replication-incompetent vaccine proposals while two replication-competent (live-attenuated) HSV vaccine are undergoing human testing. [ citation needed ] A genomic study of the herpes simplex type 1 virus confirmed the human migration pattern theory known as the out-of-Africa hypothesis .

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WHO Model List of Essential Medicines

The WHO Model List of Essential Medicines (aka Essential Medicines List or EML ), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health system . The list is frequently used by countries to help develop their own local lists of essential medicines . As of 2016 [ update ] , more than 155 countries have created national lists of essential medicines based on the World Health Organization's model list. This includes both developed and developing countries. The list is divided into core items and complementary items. The core items are deemed to be the most cost-effective options for key health problems and are usable with little additional health care resources. The complementary items either require additional infrastructure such as specially trained health care providers or diagnostic equipment or have a lower cost–benefit ratio . About 25% of items are in the complementary list. Some medications are listed as both core and complementary. While most medications on the list are available as generic products , being under patent does not preclude inclusion. The first list was published in 1977 and included 208 medications. The WHO updates the list every two years. There are 306 medications in the 14th list in 2005, 410 in the 19th list in 2015, 433 in the 20th list in 2017, 460 in the 21st list in 2019, and 479 in the 22nd list in 2021. Various national lists contain between 334 and 580 medications. The Essential Medicines List (EML) was updated in July 2023 to its 23rd edition. This list contains 1200 recommendations for 591 drugs and 103 therapeutic equivalents. A separate list for children up to 12 years of age, known as the WHO Model List of Essential Medicines for Children (EMLc), was created in 2007 and is in its 9th edition. It was created to make sure that the needs of children were systematically considered such as availability of proper formulations . Everything in the children's list is also included in the main list. The list and notes are based on the 19th to 23rd edition of the main list. Therapeutic alternatives with similar clinical performance are listed for some medicines and they may be considered for national essential medicines lists. The 9th Essential Medicines List for Children was updated in July 2023. Note: An α indicates a medicine is on the complementary list. Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary: Complementary:Complementary:Complementary:Complementary: Complementary: Complementary: Reserve antibiotics are last-resort antibiotics. The EML antibiotic book was published in 2022. Complementary: Complementary: Complementary: Complementary: Complementary: Complementary: No listings in this section.Complementary: Complementary:Complementary:Complementary:Complementary: Reserve antibiotics are last-resort antibiotics. The EML antibiotic book was published in 2022. Complementary: Complementary:Complementary:Reserve antibiotics are last-resort antibiotics. The EML antibiotic book was published in 2022. Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary: Complementary:Complementary:Complementary:Complementary:Complementary:No listings in this section.Complementary: Complementary: Complementary: Complementary: Complementary: Complementary:Complementary:Complementary: Complementary: Complementary: Complementary: Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary: Complementary: Complementary:Complementary:Complementary:Complementary:Complementary: Complementary:Complementary: Complementary:Complementary:Complementary:Complementary: Complementary: Complementary: Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary:Complementary: Complementary: Complementary:Complementary:Complementary:Complementary: No listings in this section. Complementary: Complementary: Complementary: Complementary:Complementary:No listings in this section.Complementary:Complementary:Complementary:Complementary:Complementary:Recommendations for all Recommendations for certain regions Recommendations for some high-risk populations Recommendations for immunization programmes with certain characteristicsRecommendations for all Recommendations for certain regions Recommendations for some high-risk populations Recommendations for immunization programmes with certain characteristicsComplementary:Complementary: Complementary:Complementary:Complementary:Complementary: Complementary:Complementary:Complementary:Complementary:Complementary: Complementary:Complementary:Complementary:Complementary:Complementary:Complementary: Complementary:Complementary:Complementary:An α indicates the medicine is on the complementary list for which specialized diagnostic or monitoring or training is needed. An item may also be listed as complementary on the basis of higher costs or a less attractive cost-benefit ratio .

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Dengue virus

Dengue virus ( DENV ) is the cause of dengue fever . It is a mosquito -borne, single positive-stranded RNA virus of the family Flaviviridae ; genus Flavivirus . Four serotypes of the virus have been found, and a reported fifth has yet to be confirmed, all of which can cause the full spectrum of disease. Nevertheless, scientists' understanding of dengue virus may be simplistic as, rather than distinct antigenic groups, a continuum appears to exist. This same study identified 47 strains of dengue virus . Additionally, coinfection with and lack of rapid tests for Zika virus and chikungunya complicate matters in real-world infections. Dengue virus has increased dramatically within the last 20 years, becoming one of the worst mosquito-borne human pathogens that tropical countries have to deal with. Current estimates indicate that as many as 390 million infections occur each year, and many dengue infections are increasingly understood to be asymptomatic or subclinical. Based on the analysis of the envelope protein, at least three genotypes (1 to 3) are known. In 2013, a fourth serotype was reported. A single report of a fifth serotype DEN-5 in 2015 has not been replicated or further reported on. The rate of nucleotide substitution for this virus has been estimated to be 6.5 × 10 −4 per nucleotide per year, a rate similar to other RNA viruses. The American African genotype has been estimated to have evolved between 1907 and 1949. This period includes World War I and World War II , which were associated with considerable movement of populations and environmental disturbance, factors known to promote the evolution of new vector-borne viral species . [ citation needed ] A Bayesian analysis of all four serotypes estimated that their most recent common ancestor existed about 340 AD (95% confidence interval: 280 BC–850 AD). Until a few hundred years ago, dengue virus was transmitted in sylvatic cycles in Africa , Southeast Asia and South Asia between mosquitoes of the genus Aedes and nonhuman primates , with rare emergences into human populations. The global spread of dengue virus , however, has followed its emergence from sylvatic cycles and the primary lifecycle now exclusively involves transmission between humans and Aedes mosquitoes. Vertical transmission from mosquito to mosquito has also been observed in some vector species. Dogs have been found to be infected by the virus, but more research is needed to determine if dogs or other animals can serve as reservoirs or are just incidental hosts. Recent findings suggest that as the virus infects human cells, host homeostatic processes such as autophagy and ER stress response, not to mention apoptosis, are triggered depending on the infected cell type. The activation of autophagy and ER stress during infection enhances virus reproduction. Attempts to provide detailed summaries of the life cycle of dengue at the cellular level are published in review articles from different research groups. The DENV genome is about 11000 bases of positive-sense, single-stranded RNA (ssRNA) that codes for three structural proteins ( capsid protein C, membrane protein M, envelope protein E) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5). It also includes short noncoding regions on both the 5' and 3' ends. The DENV E (envelope) protein, found as a dimer on the surface of the mature viral particle, is important in the initial attachment of this particle to the host cell. Each E protein monomer comprises three ectodomains, ED1 to ED3, and a transmembrane segment. ED2 includes the dimerization interface, two glycosylation sites, and the peptide of fusion with the cellular membrane. ED3 is a continuous polypeptide segment; its fold is compact and immunoglobulin-like. Dengue virus is transmitted by species of the mosquito genus Aedes . Several molecules that interact with the viral E protein (ICAM3-grabbing nonintegrin, CD209, Rab 5, GRP 78, and the mannose receptor ) have been shown to be important factors mediating attachment and viral entry. The membrane form of ribosomal protein SA may also be involved in the attachment. E protein is known to contain physicochemically conserved B cells and T cells specific epitopes, which can be exploited to design vaccine. Recombinant domains of the E protein are used as well-defined antigens in the serological detection of antibodies directed against dengue virus and as immunogens in vaccine candidates. The DENV prM (membrane) protein, which is important in the formation and maturation of the viral particle, consists of seven antiparallel β-strands stabilized by three disulfide bonds. The glycoprotein shell of the mature DENV virion consists of 180 copies each of the E and M proteins. The immature virion starts out with the E and prM proteins forming 90 heterodimers that give a spiky exterior to the viral particle. This immature viral particle buds into the endoplasmic reticulum and eventually travels via the secretory pathway to the Golgi apparatus. As the virion passes through the trans-Golgi network, it is exposed to low pH. This acidic environment causes a conformational change in the E protein, which disassociates it from the prM protein and causes it to form E homodimers, which lie flat against the viral surface, giving the maturing virion a smooth appearance. During this maturation, pr peptide is cleaved from the M peptide by the host protease, furin . The M protein then acts as a transmembrane protein under the E-protein shell of the mature virion. The pr peptide stays associated with the E protein until the viral particle is released into the extracellular environment. This pr peptide acts like a cap, covering the hydrophobic fusion loop of the E protein until the viral particle has exited the cell. The DENV NS3 is a serine protease, as well as an RNA helicase and RTPase/NTPase. The protease domain consists of six β-strands arranged into two β-barrels formed by residues 1–180 of the protein. The catalytic triad (His-51, Asp-75 and Ser-135) is found between these two β-barrels, and activity is dependent on the presence of a 43 amino acid segment of the NS2B cofactor. This cofactor wraps around the NS3 protease domain and becomes part of the active site. The remaining NS2B residues before and after the cofactor region contain helical domains involved in membrane binding. The remaining NS3 residues (180–618) form the three subdomains of the DENV helicase. A six-stranded parallel β-sheet surrounded by four α-helices makes up subdomains I and II, and subdomain III is composed of four α-helices surrounded by three shorter α-helices and two antiparallel β-strands. DENV NS4A is a nonstructural protein involved in altering cell membrane curvature and induction of autophagy. In addition to its membrane altering property, NS4A is a scaffold for the virus replication complex and undergoes oligomerization. Mutations of NS4A that affect interaction with NS4B abolished or severely reduced virus replication indicating the importance of NS4A and its interaction with NS4B in dengue reproduction. The DENV NS5 protein is a 900-residue peptide with a methyltransferase domain at its N-terminal end (residues 1–296) and a RNA-dependent RNA polymerase (RdRp) at its C-terminal end (residues 320–900). The methyltransferase domain consists of an α/β/β sandwich flanked by N-and C-terminal subdomains. The DENV RdRp is similar to other RdRps containing palm, finger, and thumb subdomains and a GDD motif for incorporating nucleotides. Crystal structures of complexes between antibodies and either the ectodomain (sE) of the viral E protein or its domain 3 (ED3) have helped understand the molecular bases of the virus recognition and neutralization. Some of the epitopes are partially or totally inaccessible in the known structure of the mature virion. The corresponding antibodies are, therefore, assumed to bind to alternate or transitional conformations of the virus at 37 °C. [ citation needed ]The DENV E (envelope) protein, found as a dimer on the surface of the mature viral particle, is important in the initial attachment of this particle to the host cell. Each E protein monomer comprises three ectodomains, ED1 to ED3, and a transmembrane segment. ED2 includes the dimerization interface, two glycosylation sites, and the peptide of fusion with the cellular membrane. ED3 is a continuous polypeptide segment; its fold is compact and immunoglobulin-like. Dengue virus is transmitted by species of the mosquito genus Aedes . Several molecules that interact with the viral E protein (ICAM3-grabbing nonintegrin, CD209, Rab 5, GRP 78, and the mannose receptor ) have been shown to be important factors mediating attachment and viral entry. The membrane form of ribosomal protein SA may also be involved in the attachment. E protein is known to contain physicochemically conserved B cells and T cells specific epitopes, which can be exploited to design vaccine. Recombinant domains of the E protein are used as well-defined antigens in the serological detection of antibodies directed against dengue virus and as immunogens in vaccine candidates. The DENV prM (membrane) protein, which is important in the formation and maturation of the viral particle, consists of seven antiparallel β-strands stabilized by three disulfide bonds. The glycoprotein shell of the mature DENV virion consists of 180 copies each of the E and M proteins. The immature virion starts out with the E and prM proteins forming 90 heterodimers that give a spiky exterior to the viral particle. This immature viral particle buds into the endoplasmic reticulum and eventually travels via the secretory pathway to the Golgi apparatus. As the virion passes through the trans-Golgi network, it is exposed to low pH. This acidic environment causes a conformational change in the E protein, which disassociates it from the prM protein and causes it to form E homodimers, which lie flat against the viral surface, giving the maturing virion a smooth appearance. During this maturation, pr peptide is cleaved from the M peptide by the host protease, furin . The M protein then acts as a transmembrane protein under the E-protein shell of the mature virion. The pr peptide stays associated with the E protein until the viral particle is released into the extracellular environment. This pr peptide acts like a cap, covering the hydrophobic fusion loop of the E protein until the viral particle has exited the cell. The DENV NS3 is a serine protease, as well as an RNA helicase and RTPase/NTPase. The protease domain consists of six β-strands arranged into two β-barrels formed by residues 1–180 of the protein. The catalytic triad (His-51, Asp-75 and Ser-135) is found between these two β-barrels, and activity is dependent on the presence of a 43 amino acid segment of the NS2B cofactor. This cofactor wraps around the NS3 protease domain and becomes part of the active site. The remaining NS2B residues before and after the cofactor region contain helical domains involved in membrane binding. The remaining NS3 residues (180–618) form the three subdomains of the DENV helicase. A six-stranded parallel β-sheet surrounded by four α-helices makes up subdomains I and II, and subdomain III is composed of four α-helices surrounded by three shorter α-helices and two antiparallel β-strands. DENV NS4A is a nonstructural protein involved in altering cell membrane curvature and induction of autophagy. In addition to its membrane altering property, NS4A is a scaffold for the virus replication complex and undergoes oligomerization. Mutations of NS4A that affect interaction with NS4B abolished or severely reduced virus replication indicating the importance of NS4A and its interaction with NS4B in dengue reproduction. The DENV NS5 protein is a 900-residue peptide with a methyltransferase domain at its N-terminal end (residues 1–296) and a RNA-dependent RNA polymerase (RdRp) at its C-terminal end (residues 320–900). The methyltransferase domain consists of an α/β/β sandwich flanked by N-and C-terminal subdomains. The DENV RdRp is similar to other RdRps containing palm, finger, and thumb subdomains and a GDD motif for incorporating nucleotides. Crystal structures of complexes between antibodies and either the ectodomain (sE) of the viral E protein or its domain 3 (ED3) have helped understand the molecular bases of the virus recognition and neutralization. Some of the epitopes are partially or totally inaccessible in the known structure of the mature virion. The corresponding antibodies are, therefore, assumed to bind to alternate or transitional conformations of the virus at 37 °C. [ citation needed ]Common names for dengue fever include breakbone fever , vomiting and dandy fever; dengue hemorrhagic fever and dengue shock syndrome are the severe forms. Dengue is found in tropical and subtropical climates worldwide, mostly in urban and semiurban areas. People of all ages who are exposed to infected mosquitoes are at risk of developing dengue fever. The disease occurs most often during the rainy season in tropical countries in Southeast Asia , South Asia and South America , with high numbers of infected mosquitoes. The virus is transmitted to humans through the bites of infected female mosquitoes, though humans are not capable of transmitting the disease and are not contagious. The incubation period is 3 to 14 days, while the period of the illness is 3–7 days. Signs and symptoms may include severe headache; retro-orbital pain; muscle, joint, and bone pain; macular or maculopapular rash; and minor hemorrhagic manifestations, including petechiae, ecchymosis, purpura, epistaxis, bleeding gums, hematuria, or a positive tourniquet test result. A recent systematic review and meta-analysis showed that allergic symptoms are one of the core symptoms that are highly associated with dengue severity. Dengue virus' (DENV) E envelope protein binds to a cellular receptor. The exact nature of the cellular receptor has not been fully elucidated. DENV undergoes endocytosis. Acidification of the endosome leads to a conformational change of E, exposing a fusion peptide sequence that facilitates fusion of the envelope with the endosomal membrane, releasing the virion capsid into the cytoplasm. Uncoating occurs in the cytoplasm Host translational machinery (ribosomes) translates the (+)ssRNA into a single polypeptide Cellular and viral proteinases cleave the polypeptide into 10 proteins (E, M, C and 7 nonstructural/enzymatic proteins) while embedded on the ER membrane. As soon as functional RNA-dependent RNA polymerase is synthesized, RNA replication can commence. Synthesis is asymmetrical, making 10 times more of the positive-sense strand than the negative. Assembly occurs on intracellular membranes, which bud into the ER (forming the envelope from the ER membrane). Subsequent budding from the ER through the Golgi and into vesicles allows maturation via posttranslational modifications, e.g. glycosylation and pH transformational rearrangements Egress occurs via exocytosis Some people develop more severe forms of dengue, such as dengue hemorrhagic fever. Different strains of viruses interacting with people with different immune backgrounds lead to a complex interaction. Among the possible causes are cross-serotypic immune response, through a mechanism known as antibody-dependent enhancement , which happens when a person who has been previously infected with dengue gets infected for the second, third, or fourth time. The previous antibodies to the old strain of dengue virus now interfere with the immune response to the current strain, paradoxically leading to more virus entry and uptake. Some people develop more severe forms of dengue, such as dengue hemorrhagic fever. Different strains of viruses interacting with people with different immune backgrounds lead to a complex interaction. Among the possible causes are cross-serotypic immune response, through a mechanism known as antibody-dependent enhancement , which happens when a person who has been previously infected with dengue gets infected for the second, third, or fourth time. The previous antibodies to the old strain of dengue virus now interfere with the immune response to the current strain, paradoxically leading to more virus entry and uptake. In recent years, many studies have shown that flaviviruses, especially dengue virus , has the ability to inhibit the innate immune response during the infection. Indeed, dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. [ citation needed ] These proteins act on two levels : NS4B is a small, hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha & beta. In fact, as the activity of Tyk2 kinase decreases in association with dengue virus , so too does STAT 1 phosphorylation. Furthermore, the innate immune system's response to the virus is further damped as expression of interferon-stimulating gene(s) (ISG) is restricted by the aforementioned 'NS4B' protein. NS2A and NS4A cofactor may also take part in the STAT 1 inhibition. NS5 - the presence of this 105-kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. When NS5 is cleaved with NS4B by a protease (NS2B3), it can degrade STAT2. In fact, after the cleavage of NS5 by the protease, an E3 ligase association with STAT2 occurs, and the E3 ligase targets STAT2 for the degradation. NS2B3-b protease complex is a proteolytic core consisting of the last 40 amino acids of NS2B and the first 180 amino acids of NS3. Cleavage of the NS2B3 precursor activates the protease complex. This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter; NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3. The NS2B3 protease complex inhibits (by cleaving) protein MITA which allows the IRF3 activation. Dengue virus is transmitted by the mosquito species Aedes aegypti , which produces saliva that contains over 100 unique proteins, including the protein family D7. Scientists used to believe that A. aegypti saliva, when being transmitted, actually enhanced dengue virus in the body. The mosquito's saliva was thought to make the virus spread faster due to the weakened immune response of its host. However, a current study has found that the protein D7 hinders the virus transmission into the host cells. The immune responses of antibodies that are trying to fight off the foreign virus actually increase transmission and make the infection worse. Levels of protein D7 are more prevalent in salivary glands of dengue-infected mosquitoes compared to those uninfected ones. D7 is found in mosquito saliva and was thought to assist the process of blood feeding. Despite the prior assumptions, D7 can modulate the host cell and act against the virus to prevent viral infection. Unfortunately, D7 proteins provoke immune responses, which raise anti-D7 antibody levels. These antibodies inhibit the function of D7 proteins, which enhance transmission of dengue virus [ citation needed ] . Although immune responses against D7 proteins might impair their antiviral activity, a study showed that non-DENV subjects have slightly higher anti-D7 IgG levels than infected ones, although it was not statistically significant. Thus, more studies over D7 protein family are needed do elucidate its role on DENV infection and its applicability in medicine. Two types of dengue vaccine have been approved and are commercially available. On 5 December 2022 the European Medicines Agency approved Qdenga, a live tetravalent attenuated vaccine for adults, adolescents and children from four years of age. The 2016 vaccine Dengvaxia is only recommended in individuals who have been previously infected, or in populations with a high rate of prior infection by age nine. Dengvaxia has been approved in 11 countries (Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore). Several vaccines are under development by private and public researchers. Developing a vaccine against the disease is challenging. With four different serotypes of the virus that can cause the disease, the vaccine must immunize against all four types to be effective. Vaccination against only one serotype could possibly lead to severe dengue hemorrhagic shock when infected with another serotype due to antibody-dependent enhancement. When infected with dengue virus , the immune system produces cross-reactive antibodies that provide immunity to that particular serotype. However, these antibodies are incapable of neutralizing other serotypes upon reinfection and actually increase viral replication . When macrophages consume the 'neutralized' virus, the virus is able to replicate within the macrophage, causing disease. These cross-reactive, ineffective antibodies ease access of the virus into macrophages, which induces more severe disease (dengue hemorrhagic fever, dengue shock syndrome). A common problem faced in dengue-endemic regions is when mothers become infected with dengue; after giving birth, offspring carry the immunity from their mother and are susceptible to hemorrhagic fever if infected with any of the other three serotypes. One vaccine was in phase III trials in 2012 and planning for vaccine usage and effectiveness surveillance had started. In 2009, Sanofi-Pasteur started building a new facility in Neuville-sur-Saône ' ( fr ) , a suburb of Lyon (France). This unit produces four-serotype vaccine for phase III trials. In September 2014, the Sanofi-Pasteur CEO gave early results of the phase III trial efficacy study in Latin America. The efficacy per serotype (ST) varied widely, 42.3% for ST2, 50.3% for ST1, 74.0% for ST3, and 77.7% for ST4. The full analysis of data from the phase III Latin American-Caribbean study will be reviewed by external experts before being published in a peer-reviewed scientific journal. Primary results has to be presented at the American Society of Tropical Medicine and Hygiene Annual Meeting, held November 2–6, 2014, in New Orleans. In September 2012, one of the vaccines was reported to not have done well in clinical trials. In late 2015 and early 2016, the first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi-Pasteur, was registered in several countries for use in individuals 9–45 years of age living in endemic areas. [ citation needed ] On May 1, 2019, the U.S. Food and Drug Administration announced the approval of Dengvaxia, the first vaccine for the prevention of dengue disease caused by all dengue virus serotypes in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands. There are no approved direct antiviral treatments for Dengue fever. Most antiviral drug research for Dengue infections has focussed on inhibition of the NS2B/NS3 protease or NS5 proteins. Reported protease inhibitor approaches have focussed mainly on targeted covalent inhibitors . One drug, Balapiravir , a repurposed hepatitis C NS5 polymerase inhibitor progressed to a Phase II clinical trial before being stopped due to lack of efficacy. NS4B is a small, hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha & beta. In fact, as the activity of Tyk2 kinase decreases in association with dengue virus , so too does STAT 1 phosphorylation. Furthermore, the innate immune system's response to the virus is further damped as expression of interferon-stimulating gene(s) (ISG) is restricted by the aforementioned 'NS4B' protein. NS2A and NS4A cofactor may also take part in the STAT 1 inhibition. NS5 - the presence of this 105-kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. When NS5 is cleaved with NS4B by a protease (NS2B3), it can degrade STAT2. In fact, after the cleavage of NS5 by the protease, an E3 ligase association with STAT2 occurs, and the E3 ligase targets STAT2 for the degradation. NS2B3-b protease complex is a proteolytic core consisting of the last 40 amino acids of NS2B and the first 180 amino acids of NS3. Cleavage of the NS2B3 precursor activates the protease complex. This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter; NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3. The NS2B3 protease complex inhibits (by cleaving) protein MITA which allows the IRF3 activation. Dengue virus is transmitted by the mosquito species Aedes aegypti , which produces saliva that contains over 100 unique proteins, including the protein family D7. Scientists used to believe that A. aegypti saliva, when being transmitted, actually enhanced dengue virus in the body. The mosquito's saliva was thought to make the virus spread faster due to the weakened immune response of its host. However, a current study has found that the protein D7 hinders the virus transmission into the host cells. The immune responses of antibodies that are trying to fight off the foreign virus actually increase transmission and make the infection worse. Levels of protein D7 are more prevalent in salivary glands of dengue-infected mosquitoes compared to those uninfected ones. D7 is found in mosquito saliva and was thought to assist the process of blood feeding. Despite the prior assumptions, D7 can modulate the host cell and act against the virus to prevent viral infection. Unfortunately, D7 proteins provoke immune responses, which raise anti-D7 antibody levels. These antibodies inhibit the function of D7 proteins, which enhance transmission of dengue virus [ citation needed ] . Although immune responses against D7 proteins might impair their antiviral activity, a study showed that non-DENV subjects have slightly higher anti-D7 IgG levels than infected ones, although it was not statistically significant. Thus, more studies over D7 protein family are needed do elucidate its role on DENV infection and its applicability in medicine.Two types of dengue vaccine have been approved and are commercially available. On 5 December 2022 the European Medicines Agency approved Qdenga, a live tetravalent attenuated vaccine for adults, adolescents and children from four years of age. The 2016 vaccine Dengvaxia is only recommended in individuals who have been previously infected, or in populations with a high rate of prior infection by age nine. Dengvaxia has been approved in 11 countries (Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore). Several vaccines are under development by private and public researchers. Developing a vaccine against the disease is challenging. With four different serotypes of the virus that can cause the disease, the vaccine must immunize against all four types to be effective. Vaccination against only one serotype could possibly lead to severe dengue hemorrhagic shock when infected with another serotype due to antibody-dependent enhancement. When infected with dengue virus , the immune system produces cross-reactive antibodies that provide immunity to that particular serotype. However, these antibodies are incapable of neutralizing other serotypes upon reinfection and actually increase viral replication . When macrophages consume the 'neutralized' virus, the virus is able to replicate within the macrophage, causing disease. These cross-reactive, ineffective antibodies ease access of the virus into macrophages, which induces more severe disease (dengue hemorrhagic fever, dengue shock syndrome). A common problem faced in dengue-endemic regions is when mothers become infected with dengue; after giving birth, offspring carry the immunity from their mother and are susceptible to hemorrhagic fever if infected with any of the other three serotypes. One vaccine was in phase III trials in 2012 and planning for vaccine usage and effectiveness surveillance had started. In 2009, Sanofi-Pasteur started building a new facility in Neuville-sur-Saône ' ( fr ) , a suburb of Lyon (France). This unit produces four-serotype vaccine for phase III trials. In September 2014, the Sanofi-Pasteur CEO gave early results of the phase III trial efficacy study in Latin America. The efficacy per serotype (ST) varied widely, 42.3% for ST2, 50.3% for ST1, 74.0% for ST3, and 77.7% for ST4. The full analysis of data from the phase III Latin American-Caribbean study will be reviewed by external experts before being published in a peer-reviewed scientific journal. Primary results has to be presented at the American Society of Tropical Medicine and Hygiene Annual Meeting, held November 2–6, 2014, in New Orleans. In September 2012, one of the vaccines was reported to not have done well in clinical trials. In late 2015 and early 2016, the first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi-Pasteur, was registered in several countries for use in individuals 9–45 years of age living in endemic areas. [ citation needed ] On May 1, 2019, the U.S. Food and Drug Administration announced the approval of Dengvaxia, the first vaccine for the prevention of dengue disease caused by all dengue virus serotypes in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands. There are no approved direct antiviral treatments for Dengue fever. Most antiviral drug research for Dengue infections has focussed on inhibition of the NS2B/NS3 protease or NS5 proteins. Reported protease inhibitor approaches have focussed mainly on targeted covalent inhibitors . One drug, Balapiravir , a repurposed hepatitis C NS5 polymerase inhibitor progressed to a Phase II clinical trial before being stopped due to lack of efficacy.

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Biosafety level

A biosafety level ( BSL ), or pathogen/protection level , is a set of biocontainment precautions required to isolate dangerous biological agents in an enclosed laboratory facility. The levels of containment range from the lowest biosafety level 1 (BSL-1) to the highest at level 4 (BSL-4). In the United States, the Centers for Disease Control and Prevention (CDC) have specified these levels in a publication referred to as BMBL. In the European Union , the same biosafety levels are defined in a directive . In Canada the four levels are known as Containment Levels. Facilities with these designations are also sometimes given as P1 through P4 (for pathogen or protection level), as in the term P3 laboratory . At the lowest level of biosafety, precautions may consist of regular hand-washing and minimal protective equipment. At higher biosafety levels, precautions may include airflow systems, multiple containment rooms, sealed containers, positive pressure personnel suits , established protocols for all procedures, extensive personnel training, and high levels of security to control access to the facility. Health Canada reports that world-wide until 1999 there were recorded over 5,000 cases of accidental laboratory infections and 190 deaths. The first prototype Class III (maximum containment) biosafety cabinet was fashioned in 1943 by Hubert Kaempf Jr., then a U.S. Army soldier, under the direction of Arnold G. Wedum, Director (1944–1969) of Industrial Health and Safety at the United States Army Biological Warfare Laboratories , Camp Detrick , Maryland . Kaempf was tired of his MP duties at Detrick and was able to transfer to the sheet metal department working with the contractor, the H.K. Ferguson Co. On 18 April 1955, fourteen representatives met at Camp Detrick in Frederick, Maryland. The meeting was to share knowledge and experiences regarding biosafety , chemical, radiological, and industrial safety issues that were common to the operations at the three principal biological warfare (BW) laboratories of the U.S. Army. Because of the potential implication of the work conducted at biological warfare laboratories, the conferences were restricted to top level security clearances . Beginning in 1957, these conferences were planned to include non-classified sessions as well as classified sessions to enable broader sharing of biological safety information. It was not until 1964, however, that conferences were held in a government installation not associated with a biological warfare program. Over the next ten years, the biological safety conferences grew to include representatives from all federal agencies that sponsored or conducted research with pathogenic microorganisms. By 1966, it began to include representatives from universities, private laboratories, hospitals, and industrial complexes. Throughout the 1970s, participation in the conferences continued to expand and by 1983 discussions began regarding the creation of a formal organization. The American Biological Safety Association (ABSA) was officially established in 1984 and a constitution and bylaws were drafted the same year. As of 2008, ABSA includes some 1,600 members in its professional association. In 1977, Jim Peacock of the Australian Academy of Science asked Bill Snowdon, then chief of the CSIRO 's Australian Animal Health Laboratory (AAHL) if he could have the newly released United States' National Institutes of Health and the British equivalent requirements for the development of infrastructure for bio-containment reviewed by AAHL personnel with a view to recommending the adoption of one of them by Australian authorities. The review was carried out by CSIRO AAHL Project Manager Bill Curnow and CSIRO Engineer Arthur Jenkins. They drafted outcomes for each of the levels of security. AAHL was notionally classified as "substantially beyond P4". These were adopted by the Australian Academy of Science and became the basis for Australian legislation. It opened in 1985 costing AU$185 million, built on Corio Oval . The Australian Animal Health Laboratory is a Class 4/ P4 Laboratory. In 2003, the Chinese Academy of Sciences approved the construction of mainland China's first BSL-4 laboratory at the Wuhan Institute of Virology (WIV). In 2014, the WIV's National Bio-safety Laboratory was built at a cost of 300 million yuan (US$44 million), in collaboration and with assistance from the French government 's CIRI lab . In 2007 a scientific review paper stated that the Canadian Science Centre for Human and Animal Health , which was designed in the early 1990s, "has become the prototype for modern BSL4 laboratories". Starting with the 2020 COVID-19 pandemic near the facilities of the WIV, work in biocontainment facilities has been politicized, especially in the US Senate for example as the result of Rand Paul 's work. Russia asked questions on 25 October 2022 in the United Nations over the presence in Ukraine of biolabs. In April 2023, Sudan's descent into civil war caused worries at the World Health Organization over its National Public Laboratory as contending factions battled over its area and NPL staff were kicked out in favor of installing a military base at its premises. At the time, the facility contained organisms rated at BSL-2. Biosafety level 1 (BSL-1) is suitable for work with well-characterized agents which do not cause disease in healthy humans. In general, these agents should pose minimal potential hazard to laboratory personnel and the environment. At this level, precautions are limited relative to other levels. Laboratory personnel must wash their hands upon entering and exiting the lab. Research with these agents may be performed on standard open laboratory benches without the use of special containment equipment. However, eating and drinking are generally prohibited in laboratory areas. Potentially infectious material must be decontaminated before disposal, either by adding a chemical such as bleach or isopropanol or by packaging for decontamination elsewhere. Personal protective equipment is only required for circumstances where personnel might be exposed to hazardous material. BSL-1 laboratories must have a door which can be closed to limit access to the lab. However, it is not necessary for BSL-1 labs to be isolated from the general building. This level of biosafety is appropriate for work with several kinds of microorganisms including non-pathogenic strains of Escherichia coli and Staphylococcus , Bacillus subtilis , Saccharomyces cerevisiae and other organisms not suspected to contribute to human disease. Due to the relative ease and safety of maintaining a BSL-1 laboratory, these are the types of laboratories generally used as teaching spaces for high schools and colleges . At this level, all precautions used at Biosafety level 1 are followed, and some additional precautions are taken. BSL-2 differs from BSL-1 in that: Biosafety level 2 is suitable for work involving agents of moderate potential hazard to personnel and the environment. This includes various microbes that cause mild disease to humans, or are difficult to contract via aerosol in a lab setting. Examples of pathogens classified as "Risk Group 2" in the United States include hepatitis A , B , and C viruses, human immunodeficiency virus (HIV), pathogenic strains of Escherichia coli and Staphylococcus , Salmonella , Plasmodium falciparum , and Toxoplasma gondii . Notably, the European Union departs from the United States and classifies HIV and hepatitis B – G as Risk Group 3 agents best handled at BSL-3. Prions , the infectious agents that transmit prion diseases such as vCJD , are typically handled under Biosafety Level 2 or higher. This is due to the lack of any evidence of aerosol transmission and relatively higher infective dose of prion diseases, though some circumstances (such as handling animal-infective prions in a facility which cares for vulnerable animals) would require BSL-3 conditions. Biosafety level 3 is appropriate for work involving microbes which can cause serious and potentially lethal disease via the inhalation route. This type of work can be done in clinical, diagnostic, teaching, research, or production facilities. Here, the precautions undertaken in BSL-1 and BSL-2 labs are followed, as well as additional measures including: In addition, the facility which houses the BSL-3 laboratory must have certain features to ensure appropriate containment. The entrance to the laboratory must be separated from areas of the building with unrestricted traffic flow. Additionally, the laboratory must be behind two sets of self-closing doors (to reduce the risk of aerosols escaping). The construction of the laboratory is such that it can be easily cleaned. Carpets are not permitted, and any seams in the floors, walls, and ceilings are sealed to allow for easy cleaning and decontamination. Additionally, windows must be sealed, and a ventilation system installed which forces air to flow from the "clean" areas of the lab to the areas where infectious agents are handled. Air from the laboratory must be filtered before it can be recirculated. A 2015 study by USA Today journalists identified more than 200 lab sites in the U.S. that were accredited biosafety levels 3 or 4. The Proceedings of a Workshop on "Developing Norms for the Provision of Biological Laboratories in Low-Resource Contexts" provides a list of BSL-3 laboratories in those countries. Biosafety level 3 is commonly used for research and diagnostic work involving various microbes which can be transmitted by aerosols and/or cause severe disease. These include Francisella tularensis , Mycobacterium tuberculosis , Chlamydia psittaci , Venezuelan equine encephalitis virus , Eastern equine encephalitis virus , SARS-CoV-1 , MERS-CoV , Coxiella burnetii , Rift Valley fever virus , Rickettsia rickettsii , several species of Brucella , chikungunya , yellow fever virus , West Nile virus , Yersinia pestis , and SARS-CoV-2 . Biosafety level 4 (BSL-4) is the highest level of biosafety precautions, and is appropriate for work with agents that could easily be aerosol-transmitted within the laboratory and cause severe to fatal disease in humans for which there are no available vaccines or treatments. BSL-4 laboratories are generally set up to be either cabinet laboratories or protective-suit laboratories. In cabinet laboratories, all work must be done within a class III biosafety cabinet . Materials leaving the cabinet must be decontaminated by passing through an autoclave or a tank of disinfectant . The cabinets themselves are required to have seamless edges to allow for easy cleaning. Additionally, the cabinet and all materials within must be free of sharp edges to reduce the risk of damage to the gloves. In a protective-suit laboratory, all work must be done in a class II biosafety cabinet by personnel wearing a positive pressure suit . To exit the BSL-4 laboratory, personnel must pass through a chemical shower for decontamination, then a room for removing the positive-pressure suit, followed by a personal shower. Entry into the BSL-4 laboratory is restricted to trained and authorized individuals, and all persons entering and exiting the laboratory must be recorded. As with BSL-3 laboratories, BSL-4 laboratories must be separated from areas that receive unrestricted traffic. Additionally, airflow is tightly controlled to ensure that air always flows from "clean" areas of the lab to areas where work with infectious agents is being performed. The entrance to the BSL-4 lab must also employ airlocks to minimize the possibility that aerosols from the lab could be removed from the lab. All laboratory waste, including filtered air, water, and trash must also be decontaminated before it can leave the facility. Biosafety level 4 laboratories are used for diagnostic work and research on easily transmitted pathogens which can cause fatal disease. These include a number of viruses known to cause viral hemorrhagic fever such as Marburg virus , Ebola virus , Lassa virus , and Crimean-Congo hemorrhagic fever . Other pathogens handled at BSL-4 include Hendra virus , Nipah virus , and some flaviviruses . Additionally, poorly characterized pathogens which appear closely related to dangerous pathogens are often handled at this level until sufficient data are obtained either to confirm continued work at this level, or to permit working with them at a lower level. This level is also used for work with Variola virus , the causative agent of smallpox , though this work is only performed at the Centers for Disease Control and Prevention in Atlanta, United States, and the State Research Center of Virology and Biotechnology in Koltsovo, Russia. Sample-return missions that bring back to Earth samples obtained from a Category V body must be curated at facilities rated BSL-4. Because the existing BSL-4 facilities in the world do not provide the level of cleanliness necessary to such pristine samples, there is a need to design a facility dedicated to curation of restricted (potentially biohazardous ) extraterrestrial materials . The systems of such facilities must be able to contain unknown biohazards, as the sizes of any putative alien microorganisms are unknown. Ideally, it should filter particles down to 10 nanometers , and release of a particle 50 nanometers or larger is unacceptable under any circumstance. Because NASA and ESA are collaborating on the Mars Sample Return campaign, due to return samples from Mars in the early 2030s, the need for a Sample Receiving Facility (SRF) is becoming more pressing. An SRF is expected to take 7 to 10 years from design to completion, and an additional two years is recommended for the staff to become proficient and accustomed to the facilities. Biosafety level 1 (BSL-1) is suitable for work with well-characterized agents which do not cause disease in healthy humans. In general, these agents should pose minimal potential hazard to laboratory personnel and the environment. At this level, precautions are limited relative to other levels. Laboratory personnel must wash their hands upon entering and exiting the lab. Research with these agents may be performed on standard open laboratory benches without the use of special containment equipment. However, eating and drinking are generally prohibited in laboratory areas. Potentially infectious material must be decontaminated before disposal, either by adding a chemical such as bleach or isopropanol or by packaging for decontamination elsewhere. Personal protective equipment is only required for circumstances where personnel might be exposed to hazardous material. BSL-1 laboratories must have a door which can be closed to limit access to the lab. However, it is not necessary for BSL-1 labs to be isolated from the general building. This level of biosafety is appropriate for work with several kinds of microorganisms including non-pathogenic strains of Escherichia coli and Staphylococcus , Bacillus subtilis , Saccharomyces cerevisiae and other organisms not suspected to contribute to human disease. Due to the relative ease and safety of maintaining a BSL-1 laboratory, these are the types of laboratories generally used as teaching spaces for high schools and colleges . At this level, all precautions used at Biosafety level 1 are followed, and some additional precautions are taken. BSL-2 differs from BSL-1 in that: Biosafety level 2 is suitable for work involving agents of moderate potential hazard to personnel and the environment. This includes various microbes that cause mild disease to humans, or are difficult to contract via aerosol in a lab setting. Examples of pathogens classified as "Risk Group 2" in the United States include hepatitis A , B , and C viruses, human immunodeficiency virus (HIV), pathogenic strains of Escherichia coli and Staphylococcus , Salmonella , Plasmodium falciparum , and Toxoplasma gondii . Notably, the European Union departs from the United States and classifies HIV and hepatitis B – G as Risk Group 3 agents best handled at BSL-3. Prions , the infectious agents that transmit prion diseases such as vCJD , are typically handled under Biosafety Level 2 or higher. This is due to the lack of any evidence of aerosol transmission and relatively higher infective dose of prion diseases, though some circumstances (such as handling animal-infective prions in a facility which cares for vulnerable animals) would require BSL-3 conditions. Biosafety level 3 is appropriate for work involving microbes which can cause serious and potentially lethal disease via the inhalation route. This type of work can be done in clinical, diagnostic, teaching, research, or production facilities. Here, the precautions undertaken in BSL-1 and BSL-2 labs are followed, as well as additional measures including: In addition, the facility which houses the BSL-3 laboratory must have certain features to ensure appropriate containment. The entrance to the laboratory must be separated from areas of the building with unrestricted traffic flow. Additionally, the laboratory must be behind two sets of self-closing doors (to reduce the risk of aerosols escaping). The construction of the laboratory is such that it can be easily cleaned. Carpets are not permitted, and any seams in the floors, walls, and ceilings are sealed to allow for easy cleaning and decontamination. Additionally, windows must be sealed, and a ventilation system installed which forces air to flow from the "clean" areas of the lab to the areas where infectious agents are handled. Air from the laboratory must be filtered before it can be recirculated. A 2015 study by USA Today journalists identified more than 200 lab sites in the U.S. that were accredited biosafety levels 3 or 4. The Proceedings of a Workshop on "Developing Norms for the Provision of Biological Laboratories in Low-Resource Contexts" provides a list of BSL-3 laboratories in those countries. Biosafety level 3 is commonly used for research and diagnostic work involving various microbes which can be transmitted by aerosols and/or cause severe disease. These include Francisella tularensis , Mycobacterium tuberculosis , Chlamydia psittaci , Venezuelan equine encephalitis virus , Eastern equine encephalitis virus , SARS-CoV-1 , MERS-CoV , Coxiella burnetii , Rift Valley fever virus , Rickettsia rickettsii , several species of Brucella , chikungunya , yellow fever virus , West Nile virus , Yersinia pestis , and SARS-CoV-2 . Biosafety level 4 (BSL-4) is the highest level of biosafety precautions, and is appropriate for work with agents that could easily be aerosol-transmitted within the laboratory and cause severe to fatal disease in humans for which there are no available vaccines or treatments. BSL-4 laboratories are generally set up to be either cabinet laboratories or protective-suit laboratories. In cabinet laboratories, all work must be done within a class III biosafety cabinet . Materials leaving the cabinet must be decontaminated by passing through an autoclave or a tank of disinfectant . The cabinets themselves are required to have seamless edges to allow for easy cleaning. Additionally, the cabinet and all materials within must be free of sharp edges to reduce the risk of damage to the gloves. In a protective-suit laboratory, all work must be done in a class II biosafety cabinet by personnel wearing a positive pressure suit . To exit the BSL-4 laboratory, personnel must pass through a chemical shower for decontamination, then a room for removing the positive-pressure suit, followed by a personal shower. Entry into the BSL-4 laboratory is restricted to trained and authorized individuals, and all persons entering and exiting the laboratory must be recorded. As with BSL-3 laboratories, BSL-4 laboratories must be separated from areas that receive unrestricted traffic. Additionally, airflow is tightly controlled to ensure that air always flows from "clean" areas of the lab to areas where work with infectious agents is being performed. The entrance to the BSL-4 lab must also employ airlocks to minimize the possibility that aerosols from the lab could be removed from the lab. All laboratory waste, including filtered air, water, and trash must also be decontaminated before it can leave the facility. Biosafety level 4 laboratories are used for diagnostic work and research on easily transmitted pathogens which can cause fatal disease. These include a number of viruses known to cause viral hemorrhagic fever such as Marburg virus , Ebola virus , Lassa virus , and Crimean-Congo hemorrhagic fever . Other pathogens handled at BSL-4 include Hendra virus , Nipah virus , and some flaviviruses . Additionally, poorly characterized pathogens which appear closely related to dangerous pathogens are often handled at this level until sufficient data are obtained either to confirm continued work at this level, or to permit working with them at a lower level. This level is also used for work with Variola virus , the causative agent of smallpox , though this work is only performed at the Centers for Disease Control and Prevention in Atlanta, United States, and the State Research Center of Virology and Biotechnology in Koltsovo, Russia. Sample-return missions that bring back to Earth samples obtained from a Category V body must be curated at facilities rated BSL-4. Because the existing BSL-4 facilities in the world do not provide the level of cleanliness necessary to such pristine samples, there is a need to design a facility dedicated to curation of restricted (potentially biohazardous ) extraterrestrial materials . The systems of such facilities must be able to contain unknown biohazards, as the sizes of any putative alien microorganisms are unknown. Ideally, it should filter particles down to 10 nanometers , and release of a particle 50 nanometers or larger is unacceptable under any circumstance. Because NASA and ESA are collaborating on the Mars Sample Return campaign, due to return samples from Mars in the early 2030s, the need for a Sample Receiving Facility (SRF) is becoming more pressing. An SRF is expected to take 7 to 10 years from design to completion, and an additional two years is recommended for the staff to become proficient and accustomed to the facilities. Sample-return missions that bring back to Earth samples obtained from a Category V body must be curated at facilities rated BSL-4. Because the existing BSL-4 facilities in the world do not provide the level of cleanliness necessary to such pristine samples, there is a need to design a facility dedicated to curation of restricted (potentially biohazardous ) extraterrestrial materials . The systems of such facilities must be able to contain unknown biohazards, as the sizes of any putative alien microorganisms are unknown. Ideally, it should filter particles down to 10 nanometers , and release of a particle 50 nanometers or larger is unacceptable under any circumstance. Because NASA and ESA are collaborating on the Mars Sample Return campaign, due to return samples from Mars in the early 2030s, the need for a Sample Receiving Facility (SRF) is becoming more pressing. An SRF is expected to take 7 to 10 years from design to completion, and an additional two years is recommended for the staff to become proficient and accustomed to the facilities. According to a U.S. Government Accountability Office (GAO) report published on 4 October 2007, a total of 1,356 CDC/USDA registered BSL-3 facilities were identified throughout the United States. Approximately 36% of these laboratories are located in academia. 15 BSL-4 facilities were identified in the U.S. in 2007, including nine at federal labs. As of May 2021, there are 42 BSL-4 facilities in operation around the world, with a further 17 planned or under construction. The following is a list of existing BSL-4 facilities worldwide.A North Carolina Mosquito & Vector Control Association (NCMVCA) study highlighted safety concerns. In the United States, laboratories can be funded by federal, state, private, non-profit, or academically. The last accounts for 72% of the funding. High-containment labs that are registered with the Centers for Disease Control and Prevention (CDC) and the U.S. Department of Agriculture's (USDA) Select Agent Program must adhere to Department of Defense standards. Since BSL3 and 4 laboratories in the United States are regulated by either the CDC or USDA or another federal agency (depending on the pathogens they handle), no single federal agency is responsible for regulating or tracking the number of these labs. U.S. high-containment laboratories that handle pathogens which are declared as " select agents " must be inspected periodically by the CDC or USDA, adhere to certain standards, and maintain ongoing education on biosecurity and biosafety policies as mandated by law.

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Senjuti Saha

Senjuti Saha is a Bangladeshi scientist at the Child Health Research Foundation (CHRF), and board member of the Polio Transition Independent Monitoring Board (TIMB) of the World Health Organization (WHO). She is known for her lead on decoding the genome of SARS-CoV2 in Bangladesh. Saha was born and raised in Dhaka, Bangladesh. Her father Dr. Samir Kumar Saha is a microbiologist and her mother Dr. Setarunnahar Setara is a public health researcher. Senjuti Saha finished high school in Bangladesh. After finishing A level, she started her Bachelor of Science with biochemistry major at the University of Toronto . She has also received her PhD from the same institute. Senjuti saha started her career as post-doctoral research fellow at The Hospital for Sick Children in Toronto, Canada. She was also appointed as a post-doctoral researcher at the Child Health Research Center (CHRF) in Bangladesh. In 2019, she joined CHRF as scientist. Currently she is also appointed by the WHO as board member of Polio Transition Independent Monitoring Board (TIMB). In 2020, Senjuti Saha and her team decoded the genome sequence of SARS-CoV2 in Bangladesh. Prior to that, she had performed an unbiased metagenomic sequence analysis to show a correlation between pediatric meningitis and Chikungunya virus outbreak in Bangladesh.

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Chikungunya

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Louis Pasteur

Louis Pasteur ForMemRS ( / ˈ l uː i p æ ˈ s t ɜːr / , French: [ lwi pastœʁ ] ; 27 December 1822 – 28 September 1895) was a French chemist , pharmacist , and microbiologist renowned for his discoveries of the principles of vaccination , microbial fermentation , and pasteurization , the last of which was named after him. His research in chemistry led to remarkable breakthroughs in the understanding of the causes and preventions of diseases , which laid down the foundations of hygiene, public health and much of modern medicine. Pasteur's works are credited with saving millions of lives through the developments of vaccines for rabies and anthrax . He is regarded as one of the founders of modern bacteriology and has been honored as the "father of bacteriology" and the "father of microbiology " (together with Robert Koch ; the latter epithet also attributed to Antonie van Leeuwenhoek ). Pasteur was responsible for disproving the doctrine of spontaneous generation . Under the auspices of the French Academy of Sciences , his experiment demonstrated that in sterilized and sealed flasks, nothing ever developed; conversely, in sterilized but open flasks, microorganisms could grow. For this experiment, the academy awarded him the Alhumbert Prize carrying 2,500 francs in 1862. Pasteur is also regarded as one of the fathers of germ theory of diseases , which was a minor medical concept at the time. His many experiments showed that diseases could be prevented by killing or stopping germs, thereby directly supporting the germ theory and its application in clinical medicine. He is best known to the general public for his invention of the technique of treating milk and wine to stop bacterial contamination, a process now called pasteurization. Pasteur also made significant discoveries in chemistry, most notably on the molecular basis for the asymmetry of certain crystals and racemization . Early in his career, his investigation of sodium ammonium tartrate initiated the field of optical isomerism . This work had a profound effect on structural chemistry, with eventual implications for many areas including medicinal chemistry . He was the director of the Pasteur Institute , established in 1887, until his death, and his body was interred in a vault beneath the institute. Although Pasteur made groundbreaking experiments, his reputation became associated with various controversies. Historical reassessment of his notebook revealed that he practiced deception to overcome his rivals. Louis Pasteur was born on 27 December 1822, in Dole, Jura , France, to a Catholic family of a poor tanner . He was the third child of Jean-Joseph Pasteur and Jeanne-Etiennette Roqui. The family moved to Marnoz in 1826 and then to Arbois in 1827. Pasteur entered primary school in 1831. He was dyslexic and dysgraphic . He was an average student in his early years, and not particularly academic, as his interests were fishing and sketching . He drew many pastels and portraits of his parents, friends and neighbors. Pasteur attended secondary school at the Collège d'Arbois. In October 1838, he left for Paris to enroll in a boarding school , but became homesick and returned in November. In 1839, he entered the Collège Royal at Besançon to study philosophy and earned his Bachelor of Letters degree in 1840. He was appointed a tutor at the Besançon college while continuing a degree science course with special mathematics. He failed his first examination in 1841. He managed to pass the baccalauréat scientifique (general science) degree from Dijon , where he earned his Bachelor of Science in Mathematics degree (Bachelier ès Sciences Mathématiques) in 1842, but with a mediocre grade in chemistry. Later in 1842, Pasteur took the entrance test for the École Normale Supérieure . During the test, he had to fight fatigue and only felt comfortable with physics and mathematics. He passed the first set of tests, but because his ranking was low, Pasteur decided not to continue and try again next year. He went back to the Parisian boarding school to prepare for the test. He also attended classes at the Lycée Saint-Louis and lectures of Jean-Baptiste Dumas at the Sorbonne . In 1843, he passed the test with a high ranking and entered the École Normale Supérieure . In 1845 he received the licencié ès sciences degree. In 1846, he was appointed professor of physics at the Collège de Tournon (now called Lycée Gabriel-Faure ) in Ardèche . But the chemist Antoine Jérôme Balard wanted him back at the École Normale Supérieure as a graduate laboratory assistant ( agrégé préparateur ). He joined Balard and simultaneously started his research in crystallography and in 1847, he submitted his two theses, one in chemistry and the other in physics: (a) Chemistry Thesis: "Recherches sur la capacité de saturation de l'acide arsénieux. Etudes des arsénites de potasse, de soude et d'ammoniaque."; (b) Physics Thesis: "1. Études des phénomènes relatifs à la polarisation rotatoire des liquides. 2. Application de la polarisation rotatoire des liquides à la solution de diverses questions de chimie." After serving briefly as professor of physics at the Dijon Lycée in 1848, he became professor of chemistry at the University of Strasbourg , where he met and courted Marie Laurent , daughter of the university's rector in 1849. They were married on 29 May 1849, and together had five children, only two of whom survived to adulthood; the other three died of typhoid .Pasteur was appointed professor of chemistry at the University of Strasbourg in 1848, and became the chair of chemistry in 1852. In February 1854, so that he would have time to carry out work that could earn him the title of correspondent of the Institute, he got three months' paid leave with the help of a medical certificate of convenience. He extended the leave until 1 August, the date of the start of the exams. "I tell the Minister that I will go and do the examinations so as not to increase the embarrassment of the service. It is also so as not to leave to another a sum of 6 or 700 francs". In this same year 1854, he was named dean of the new faculty of sciences at University of Lille , where he began his studies on fermentation. It was on this occasion that Pasteur uttered his oft-quoted remark: " dans les champs de l'observation, le hasard ne favorise que les esprits préparés " ("In the field of observation, chance favors only the prepared mind"). In 1857, he moved to Paris as the director of scientific studies at the École Normale Supérieure where he took control from 1858 to 1867 and introduced a series of reforms to improve the standard of scientific work. The examinations became more rigid, which led to better results, greater competition, and increased prestige. Many of his decrees, however, were rigid and authoritarian, leading to two serious student revolts. During "the bean revolt" he decreed that a mutton stew, which students had refused to eat, would be served and eaten every Monday. On another occasion he threatened to expel any student caught smoking, and 73 of the 80 students in the school resigned. In 1863, he was appointed professor of geology, physics, and chemistry at the École nationale supérieure des Beaux-Arts , a position he held until his resignation in 1867. In 1867, he became the chair of organic chemistry at the Sorbonne, but he later gave up the position because of poor health. In 1867, the École Normale's laboratory of physiological chemistry was created at Pasteur's request, and he was the laboratory's director from 1867 to 1888. In Paris, he established the Pasteur Institute in 1887, in which he was its director for the rest of his life. In Pasteur's early work as a chemist , beginning at the École Normale Supérieure , and continuing at Strasbourg and Lille, he examined the chemical, optical and crystallographic properties of a group of compounds known as tartrates . He resolved a problem concerning the nature of tartaric acid in 1848. A solution of this compound derived from living things rotated the plane of polarization of light passing through it. The problem was that tartaric acid derived by chemical synthesis had no such effect, even though its chemical reactions were identical and its elemental composition was the same. Pasteur noticed that crystals of tartrates had small faces. Then he observed that, in racemic mixtures of tartrates, half of the crystals were right-handed and half were left-handed. In solution, the right-handed compound was dextrorotatory , and the left-handed one was levorotatory. Pasteur determined that optical activity related to the shape of the crystals, and that an asymmetric internal arrangement of the molecules of the compound was responsible for twisting the light. The (2 R ,3 R )- and (2 S ,3 S )- tartrates were isometric, non-superposable mirror images of each other. This was the first time anyone had demonstrated molecular chirality , and also the first explanation of isomerism . Some historians consider Pasteur's work in this area to be his "most profound and most original contributions to science", and his "greatest scientific discovery." Pasteur was motivated to investigate fermentation while working at Lille. In 1856 a local wine manufacturer, M. Bigot, whose son was one of Pasteur's students, sought for his advice on the problems of making beetroot alcohol and souring. Pasteur began his research in the topic by repeating and confirming works of Theodor Schwann , who demonstrated a decade earlier that yeast were alive. According to his son-in-law, René Vallery-Radot, in August 1857 Pasteur sent a paper about lactic acid fermentation to the Société des Sciences de Lille, but the paper was read three months later. A memoire was subsequently published on 30 November 1857. In the memoir, he developed his ideas stating that: "I intend to establish that, just as there is an alcoholic ferment, the yeast of beer, which is found everywhere that sugar is decomposed into alcohol and carbonic acid, so also there is a particular ferment, a lactic yeast , always present when sugar becomes lactic acid ." Pasteur also wrote about alcoholic fermentation. It was published in full form in 1858. Jöns Jacob Berzelius and Justus von Liebig had proposed the theory that fermentation was caused by decomposition. Pasteur demonstrated that this theory was incorrect, and that yeast was responsible for fermentation to produce alcohol from sugar. He also demonstrated that, when a different microorganism contaminated the wine, lactic acid was produced, making the wine sour. In 1861, Pasteur observed that less sugar fermented per part of yeast when the yeast was exposed to air. The lower rate of fermentation aerobically became known as the Pasteur effect . Pasteur's research also showed that the growth of micro-organisms was responsible for spoiling beverages, such as beer, wine and milk. With this established, he invented a process in which liquids such as milk were heated to a temperature between 60 and 100 °C. This killed most bacteria and moulds already present within them. Pasteur and Claude Bernard completed tests on blood and urine on 20 April 1862. Pasteur patented the process, to fight the "diseases" of wine, in 1865. The method became known as pasteurization , and was soon applied to beer and milk. Beverage contamination led Pasteur to the idea that micro-organisms infecting animals and humans cause disease. He proposed preventing the entry of micro-organisms into the human body, leading Joseph Lister to develop antiseptic methods in surgery. In 1866, Pasteur published Etudes sur le Vin , about the diseases of wine, and he published Etudes sur la Bière in 1876, concerning the diseases of beer. In the early 19th century, Agostino Bassi had shown that muscardine was caused by a fungus that infected silkworms. Since 1853, two diseases called pébrine and flacherie had been infecting great numbers of silkworms in southern France, and by 1865 they were causing huge losses to farmers. In 1865, Pasteur went to Alès and worked for five years until 1870. Silkworms with pébrine were covered in corpuscles. In the first three years, Pasteur thought that the corpuscles were a symptom of the disease. In 1870, he concluded that the corpuscles were the cause of pébrine (it is now known that the cause is a microsporidian ). Pasteur also showed that the disease was hereditary. Pasteur developed a system to prevent pébrine: after the female moths laid their eggs, the moths were turned into a pulp. The pulp was examined with a microscope, and if corpuscles were observed, the eggs were destroyed. Pasteur concluded that bacteria caused flacherie. The primary cause is currently thought to be viruses. The spread of flacherie could be accidental or hereditary. Hygiene could be used to prevent accidental flacherie. Moths whose digestive cavities did not contain the microorganisms causing flacherie were used to lay eggs, preventing hereditary flacherie. Following his fermentation experiments, Pasteur demonstrated that the skin of grapes was the natural source of yeasts, and that sterilized grapes and grape juice never fermented. He drew grape juice from under the skin with sterilized needles, and also covered grapes with sterilized cloth. Both experiments could not produce wine in sterilized containers. His findings and ideas were against the prevailing notion of spontaneous generation . He received a particularly stern criticism from Félix Archimède Pouchet , who was director of the Rouen Museum of Natural History . To settle the debate between the eminent scientists, the French Academy of Sciences offered the Alhumbert Prize carrying 2,500 francs to whoever could experimentally demonstrate for or against the doctrine. Pouchet stated that air everywhere could cause spontaneous generation of living organisms in liquids. In the late 1850s, he performed experiments and claimed that they were evidence of spontaneous generation. Francesco Redi and Lazzaro Spallanzani had provided some evidence against spontaneous generation in the 17th and 18th centuries, respectively. Spallanzani's experiments in 1765 suggested that air contaminated broths with bacteria. In the 1860s, Pasteur repeated Spallanzani's experiments, but Pouchet reported a different result using a different broth. Pasteur performed several experiments to disprove spontaneous generation. He placed boiled liquid in a flask and let hot air enter the flask. Then he closed the flask, and no organisms grew in it. In another experiment, when he opened flasks containing boiled liquid, dust entered the flasks, causing organisms to grow in some of them. The number of flasks in which organisms grew was lower at higher altitudes, showing that air at high altitudes contained less dust and fewer organisms. Pasteur also used swan neck flasks containing a fermentable liquid. Air was allowed to enter the flask via a long curving tube that made dust particles stick to it. Nothing grew in the broths unless the flasks were tilted, making the liquid touch the contaminated walls of the neck. This showed that the living organisms that grew in such broths came from outside, on dust, rather than spontaneously generating within the liquid or from the action of pure air. These were some of the most important experiments disproving the theory of spontaneous generation. Pasteur gave a series of five presentations of his findings before the French Academy of Sciences in 1881, which were published in 1882 as Mémoire Sur les corpuscules organisés qui existent dans l'atmosphère: Examen de la doctrine des générations spontanées ( Account of Organized Corpuscles Existing in the Atmosphere: Examining the Doctrine of Spontaneous Generation ). Pasteur won the Alhumbert Prize in 1862. He concluded that: Never will the doctrine of spontaneous generation recover from the mortal blow of this simple experiment. There is no known circumstance in which it can be confirmed that microscopic beings came into the world without germs, without parents similar to themselves. In 1865, Jean-Baptiste Dumas , chemist, senator and former Minister of Agriculture and Commerce, asked Pasteur to study a new disease that was decimating silkworm farms from the south of France and Europe, the pébrine , characterized on a macroscopic scale by black spots and on a microscopic scale by the " Cornalia corpuscles". Pasteur accepted and made five long stays in Alès , between 7 June 1865 and 1869. Arriving in Alès, Pasteur familiarized himself with pébrine and also with another disease of the silkworm, known earlier than pebrine: flacherie or dead-flat disease. Contrary, for example, to Quatrefages , who coined the new word pébrine , Pasteur made the mistake of believing that the two diseases were the same and even that most of the diseases of silkworms known up to that time were identical with each other and with pébrine. It was in letters of 30 April and 21 May 1867 to Dumas that he first made the distinction between pébrine and flacherie. He made another mistake: he began by denying the "parasitic" (microbial) nature of pébrine, which several scholars (notably Antoine Béchamp ) considered well established. Even a note published on 27 August 1866 by Balbiani , which Pasteur at first seemed to welcome favourably had no effect, at least immediately. "Pasteur is mistaken. He would only change his mind in the course of 1867". At a time where Pasteur had not yet understood the cause of the pébrine, he propagated an effective process to stop infections: a sample of chrysalises was chosen, they were crushed and the corpuscles were searched for in the crushed material; if the proportion of corpuscular pupae in the sample was very low, the chamber was considered good for reproduction. This method of sorting "seeds" (eggs) is close to a method that Osimo had proposed a few years earlier, but whose trials had not been conclusive. By this process, Pasteur curbs pébrine and saves many of the silk industry in the Cévennes. In 1878, at the Congrès international séricicole , Pasteur admitted that "if pébrine is overcome, flacherie still exerts its ravages". He attributed the persistence of flacherie to the fact that the farmers had not followed his advice. In 1884, Balbiani , who disregarded the theoretical value of Pasteur's work on silkworm diseases, acknowledged that his practical process had remedied the ravages of pébrine, but added that this result tended to be counterbalanced by the development of flacherie, which was less well known and more difficult to prevent. Despite Pasteur's success against pébrine, French sericulture had not been saved from damage. (See fr:Sériciculture in the French Wikipedia.) Pasteur's first work on vaccine development was on chicken cholera . He received the bacteria samples (later called Pasteurella multocida after him) from Henry Toussaint . He started the study in 1877, and by the next year, was able to maintain a stable culture using broths. After another year of continuous culturing, he found that the bacteria were less pathogenic. Some of his culture samples could no longer induce the disease in healthy chickens . In 1879, Pasteur, planning for holiday, instructed his assistant, Charles Chamberland to inoculate the chickens with fresh bacteria culture. Chamberland forgot and went on holiday himself. On his return, he injected the month-old cultures to healthy chickens. The chickens showed some symptoms of infection, but instead of the infections being fatal, as they usually were, the chickens recovered completely. Chamberland assumed an error had been made, and wanted to discard the apparently faulty culture, but Pasteur stopped him. Pasteur injected the freshly recovered chickens with fresh bacteria that normally would kill other chickens; the chickens no longer showed any sign of infection. It was clear to him that the weakened bacteria had caused the chickens to become immune to the disease. In December 1880, Pasteur presented his results to the French Academy of Sciences as " Sur les maladies virulentes et en particulier sur la maladie appelée vulgairement choléra des poules (On virulent diseases, and in particular on the disease commonly called chicken cholera)" and published it in the academy's journal ( Comptes-Rendus hebdomadaires des séances de l'Académie des Sciences ). He attributed that the bacteria were weakened by contact with oxygen. He explained that bacteria kept in sealed containers never lost their virulence, and only those exposed to air in culture media could be used as vaccine. Pasteur introduced the term "attenuation" for this weakening of virulence as he presented before the academy, saying: We can diminish the microbe's virulence by changing the mode of culturing. This is the crucial point of my subject. I ask the Academy not to criticize, for the time being, the confidence of my proceedings that permit me to determine the microbe's attenuation, in order to save the independence of my studies and to better assure their progress... [In conclusion] I would like to point out to the Academy two main consequences to the facts presented: the hope to culture all microbes and to find a vaccine for all infectious diseases that have repeatedly afflicted humanity, and are a major burden on agriculture and breeding of domestic animals. In fact, Pasteur's vaccine against chicken cholera was not regular in its effects and was a failure. In the 1870s, he applied this immunization method to anthrax , which affected cattle , and aroused interest in combating other diseases. Pasteur cultivated bacteria from the blood of animals infected with anthrax. When he inoculated animals with the bacteria, anthrax occurred, proving that the bacteria was the cause of the disease. Many cattle were dying of anthrax in "cursed fields". Pasteur was told that sheep that died from anthrax were buried in the field. Pasteur thought that earthworms might have brought the bacteria to the surface. He found anthrax bacteria in earthworms' excrement, showing that he was correct. He told the farmers not to bury dead animals in the fields. Pasteur had been trying to develop the anthrax vaccine since 1877, soon after Robert Koch's discovery of the bacterium. On 12 July 1880, Henri Bouley read before the French Academy of Sciences a report from Henry Toussaint , a veterinary surgeon , who was not member of the academy. Toussaint had developed anthrax vaccine by killing the bacilli by heating at 55 °C for 10  minutes. He tested on eight dogs and 11 sheep, half of which died after inoculation. It was not a great success. Upon hearing the news, Pasteur immediately wrote to the academy that he could not believe that dead vaccine would work and that Toussaint's claim "overturns all the ideas I had on viruses, vaccines, etc." Following Pasteur's criticism, Toussaint switched to carbolic acid to kill anthrax bacilli and tested the vaccine on sheep in August 1880. Pasteur thought that this type of killed vaccine should not work because he believed that attenuated bacteria used up nutrients that the bacteria needed to grow. He thought oxidizing bacteria made them less virulent. But Pasteur found that anthrax bacillus was not easily weakened by culturing in air as it formed spores – unlike chicken cholera bacillus. In early 1881, he discovered that growing anthrax bacilli at about 42 °C made them unable to produce spores, and he described this method in a speech to the French Academy of Sciences on 28 February. On 21 March, he announced successful vaccination of sheep. To this news, veterinarian Hippolyte Rossignol proposed that the Société d'agriculture de Melun organize an experiment to test Pasteur's vaccine. Pasteur signed agreement of the challenge on 28 April. A public experiment was conducted in May at Pouilly-le-Fort. 58 sheep, 2 goats and 10 cattle were used, half of which were given the vaccine on 5 and 17 May; while the other half was untreated. All the animals were injected with the fresh virulent culture of anthrax bacillus on 31 May. The official result was observed and analysed on 2 June in the presence of over 200 spectators. All cattle survived, vaccinated or not. Pasteur had bravely predicted: "I hypothesized that the six vaccinated cows would not become very ill, while the four unvaccinated cows would perish or at least become very ill." However, all vaccinated sheep and goats survived, while unvaccinated ones had died or were dying before the viewers. His report to the French Academy of Sciences on 13 June concludes: [By] looking at everything from the scientific point of view, the development of a vaccination against anthrax constitutes significant progress beyond the first vaccine developed by Jenner, since the latter had never been obtained experimentally. Pasteur did not directly disclose how he prepared the vaccines used at Pouilly-le-Fort. Although his report indicated it as a "live vaccine", his laboratory notebooks show that he actually used potassium dichromate -killed vaccine, as developed by Chamberland, quite similar to Toussaint's method. The notion of a weak form of a disease causing immunity to the virulent version was not new; this had been known for a long time for smallpox . Inoculation with smallpox ( variolation ) was known to result in a much less severe disease, and greatly reduced mortality, in comparison with the naturally acquired disease. Edward Jenner had also studied vaccination using cowpox ( vaccinia ) to give cross-immunity to smallpox in the late 1790s, and by the early 1800s vaccination had spread to most of Europe. The difference between smallpox vaccination and anthrax or chicken cholera vaccination was that the latter two disease organisms had been artificially weakened, so a naturally weak form of the disease organism did not need to be found. This discovery revolutionized work in infectious diseases, and Pasteur gave these artificially weakened diseases the generic name of " vaccines ", in honour of Jenner's discovery. In 1876, Robert Koch had shown that Bacillus anthracis caused anthrax. In his papers published between 1878 and 1880, Pasteur only mentioned Koch's work in a footnote. Koch met Pasteur at the Seventh International Medical Congress in 1881. A few months later, Koch wrote that Pasteur had used impure cultures and made errors. In 1882, Pasteur replied to Koch in a speech, to which Koch responded aggressively. Koch stated that Pasteur tested his vaccine on unsuitable animals and that Pasteur's research was not properly scientific. In 1882, Koch wrote "On the Anthrax Inoculation", in which he refuted several of Pasteur's conclusions about anthrax and criticized Pasteur for keeping his methods secret, jumping to conclusions, and being imprecise. In 1883, Pasteur wrote that he used cultures prepared in a similar way to his successful fermentation experiments and that Koch misinterpreted statistics and ignored Pasteur's work on silkworms. In 1882, Pasteur sent his assistant Louis Thuillier to southern France because of an epizootic of swine erysipelas . Thuillier identified the bacillus that caused the disease in March 1883. Pasteur and Thuillier increased the bacillus's virulence after passing it through pigeons. Then they passed the bacillus through rabbits, weakening it and obtaining a vaccine. Pasteur and Thuillier incorrectly described the bacterium as a figure-eight shape. Roux described the bacterium as stick-shaped in 1884. Pasteur produced the first vaccine for rabies by growing the virus in rabbits, and then weakening it by drying the affected nerve tissue. The rabies vaccine was initially created by Emile Roux , a French doctor and a colleague of Pasteur, who had produced a killed vaccine using this method. The vaccine had been tested in 50 dogs before its first human trial. This vaccine was used on 9-year-old Joseph Meister , on 6 July 1885, after the boy was badly mauled by a rabid dog. This was done at some personal risk for Pasteur, since he was not a licensed physician and could have faced prosecution for treating the boy. After consulting with physicians, he decided to go ahead with the treatment. Over 11 days, Meister received 13 inoculations, each inoculation using viruses that had been weakened for a shorter period of time. Three months later he examined Meister and found that he was in good health. Pasteur was hailed as a hero and the legal matter was not pursued. Analysis of his laboratory notebooks shows that Pasteur had treated two people before his vaccination of Meister. One survived but may not actually have had rabies, and the other died of rabies. Pasteur began treatment of Jean-Baptiste Jupille on 20 October 1885, and the treatment was successful. Later in 1885, people, including four children from the United States, went to Pasteur's laboratory to be inoculated. In 1886, he treated 350 people, of which only one developed rabies. The treatment's success laid the foundations for the manufacture of many other vaccines. The first of the Pasteur Institutes was also built on the basis of this achievement. In The Story of San Michele , Axel Munthe writes of some risks Pasteur undertook in the rabies vaccine research: Pasteur himself was absolutely fearless. Anxious to secure a sample of saliva straight from the jaws of a rabid dog, I once saw him with the glass tube held between his lips draw a few drops of the deadly saliva from the mouth of a rabid bull-dog, held on the table by two assistants, their hands protected by leather gloves. Because of his study in germs, Pasteur encouraged doctors to sanitize their hands and equipment before surgery. Prior to this, few doctors or their assistants practiced these procedures. Ignaz Semmelweis and Joseph Lister had earlier practiced hand sanitizing in medical contexts in the 1860s. In Pasteur's early work as a chemist , beginning at the École Normale Supérieure , and continuing at Strasbourg and Lille, he examined the chemical, optical and crystallographic properties of a group of compounds known as tartrates . He resolved a problem concerning the nature of tartaric acid in 1848. A solution of this compound derived from living things rotated the plane of polarization of light passing through it. The problem was that tartaric acid derived by chemical synthesis had no such effect, even though its chemical reactions were identical and its elemental composition was the same. Pasteur noticed that crystals of tartrates had small faces. Then he observed that, in racemic mixtures of tartrates, half of the crystals were right-handed and half were left-handed. In solution, the right-handed compound was dextrorotatory , and the left-handed one was levorotatory. Pasteur determined that optical activity related to the shape of the crystals, and that an asymmetric internal arrangement of the molecules of the compound was responsible for twisting the light. The (2 R ,3 R )- and (2 S ,3 S )- tartrates were isometric, non-superposable mirror images of each other. This was the first time anyone had demonstrated molecular chirality , and also the first explanation of isomerism . Some historians consider Pasteur's work in this area to be his "most profound and most original contributions to science", and his "greatest scientific discovery." Pasteur was motivated to investigate fermentation while working at Lille. In 1856 a local wine manufacturer, M. Bigot, whose son was one of Pasteur's students, sought for his advice on the problems of making beetroot alcohol and souring. Pasteur began his research in the topic by repeating and confirming works of Theodor Schwann , who demonstrated a decade earlier that yeast were alive. According to his son-in-law, René Vallery-Radot, in August 1857 Pasteur sent a paper about lactic acid fermentation to the Société des Sciences de Lille, but the paper was read three months later. A memoire was subsequently published on 30 November 1857. In the memoir, he developed his ideas stating that: "I intend to establish that, just as there is an alcoholic ferment, the yeast of beer, which is found everywhere that sugar is decomposed into alcohol and carbonic acid, so also there is a particular ferment, a lactic yeast , always present when sugar becomes lactic acid ." Pasteur also wrote about alcoholic fermentation. It was published in full form in 1858. Jöns Jacob Berzelius and Justus von Liebig had proposed the theory that fermentation was caused by decomposition. Pasteur demonstrated that this theory was incorrect, and that yeast was responsible for fermentation to produce alcohol from sugar. He also demonstrated that, when a different microorganism contaminated the wine, lactic acid was produced, making the wine sour. In 1861, Pasteur observed that less sugar fermented per part of yeast when the yeast was exposed to air. The lower rate of fermentation aerobically became known as the Pasteur effect . Pasteur's research also showed that the growth of micro-organisms was responsible for spoiling beverages, such as beer, wine and milk. With this established, he invented a process in which liquids such as milk were heated to a temperature between 60 and 100 °C. This killed most bacteria and moulds already present within them. Pasteur and Claude Bernard completed tests on blood and urine on 20 April 1862. Pasteur patented the process, to fight the "diseases" of wine, in 1865. The method became known as pasteurization , and was soon applied to beer and milk. Beverage contamination led Pasteur to the idea that micro-organisms infecting animals and humans cause disease. He proposed preventing the entry of micro-organisms into the human body, leading Joseph Lister to develop antiseptic methods in surgery. In 1866, Pasteur published Etudes sur le Vin , about the diseases of wine, and he published Etudes sur la Bière in 1876, concerning the diseases of beer. In the early 19th century, Agostino Bassi had shown that muscardine was caused by a fungus that infected silkworms. Since 1853, two diseases called pébrine and flacherie had been infecting great numbers of silkworms in southern France, and by 1865 they were causing huge losses to farmers. In 1865, Pasteur went to Alès and worked for five years until 1870. Silkworms with pébrine were covered in corpuscles. In the first three years, Pasteur thought that the corpuscles were a symptom of the disease. In 1870, he concluded that the corpuscles were the cause of pébrine (it is now known that the cause is a microsporidian ). Pasteur also showed that the disease was hereditary. Pasteur developed a system to prevent pébrine: after the female moths laid their eggs, the moths were turned into a pulp. The pulp was examined with a microscope, and if corpuscles were observed, the eggs were destroyed. Pasteur concluded that bacteria caused flacherie. The primary cause is currently thought to be viruses. The spread of flacherie could be accidental or hereditary. Hygiene could be used to prevent accidental flacherie. Moths whose digestive cavities did not contain the microorganisms causing flacherie were used to lay eggs, preventing hereditary flacherie. Following his fermentation experiments, Pasteur demonstrated that the skin of grapes was the natural source of yeasts, and that sterilized grapes and grape juice never fermented. He drew grape juice from under the skin with sterilized needles, and also covered grapes with sterilized cloth. Both experiments could not produce wine in sterilized containers. His findings and ideas were against the prevailing notion of spontaneous generation . He received a particularly stern criticism from Félix Archimède Pouchet , who was director of the Rouen Museum of Natural History . To settle the debate between the eminent scientists, the French Academy of Sciences offered the Alhumbert Prize carrying 2,500 francs to whoever could experimentally demonstrate for or against the doctrine. Pouchet stated that air everywhere could cause spontaneous generation of living organisms in liquids. In the late 1850s, he performed experiments and claimed that they were evidence of spontaneous generation. Francesco Redi and Lazzaro Spallanzani had provided some evidence against spontaneous generation in the 17th and 18th centuries, respectively. Spallanzani's experiments in 1765 suggested that air contaminated broths with bacteria. In the 1860s, Pasteur repeated Spallanzani's experiments, but Pouchet reported a different result using a different broth. Pasteur performed several experiments to disprove spontaneous generation. He placed boiled liquid in a flask and let hot air enter the flask. Then he closed the flask, and no organisms grew in it. In another experiment, when he opened flasks containing boiled liquid, dust entered the flasks, causing organisms to grow in some of them. The number of flasks in which organisms grew was lower at higher altitudes, showing that air at high altitudes contained less dust and fewer organisms. Pasteur also used swan neck flasks containing a fermentable liquid. Air was allowed to enter the flask via a long curving tube that made dust particles stick to it. Nothing grew in the broths unless the flasks were tilted, making the liquid touch the contaminated walls of the neck. This showed that the living organisms that grew in such broths came from outside, on dust, rather than spontaneously generating within the liquid or from the action of pure air. These were some of the most important experiments disproving the theory of spontaneous generation. Pasteur gave a series of five presentations of his findings before the French Academy of Sciences in 1881, which were published in 1882 as Mémoire Sur les corpuscules organisés qui existent dans l'atmosphère: Examen de la doctrine des générations spontanées ( Account of Organized Corpuscles Existing in the Atmosphere: Examining the Doctrine of Spontaneous Generation ). Pasteur won the Alhumbert Prize in 1862. He concluded that: Never will the doctrine of spontaneous generation recover from the mortal blow of this simple experiment. There is no known circumstance in which it can be confirmed that microscopic beings came into the world without germs, without parents similar to themselves. In 1865, Jean-Baptiste Dumas , chemist, senator and former Minister of Agriculture and Commerce, asked Pasteur to study a new disease that was decimating silkworm farms from the south of France and Europe, the pébrine , characterized on a macroscopic scale by black spots and on a microscopic scale by the " Cornalia corpuscles". Pasteur accepted and made five long stays in Alès , between 7 June 1865 and 1869. Arriving in Alès, Pasteur familiarized himself with pébrine and also with another disease of the silkworm, known earlier than pebrine: flacherie or dead-flat disease. Contrary, for example, to Quatrefages , who coined the new word pébrine , Pasteur made the mistake of believing that the two diseases were the same and even that most of the diseases of silkworms known up to that time were identical with each other and with pébrine. It was in letters of 30 April and 21 May 1867 to Dumas that he first made the distinction between pébrine and flacherie. He made another mistake: he began by denying the "parasitic" (microbial) nature of pébrine, which several scholars (notably Antoine Béchamp ) considered well established. Even a note published on 27 August 1866 by Balbiani , which Pasteur at first seemed to welcome favourably had no effect, at least immediately. "Pasteur is mistaken. He would only change his mind in the course of 1867". At a time where Pasteur had not yet understood the cause of the pébrine, he propagated an effective process to stop infections: a sample of chrysalises was chosen, they were crushed and the corpuscles were searched for in the crushed material; if the proportion of corpuscular pupae in the sample was very low, the chamber was considered good for reproduction. This method of sorting "seeds" (eggs) is close to a method that Osimo had proposed a few years earlier, but whose trials had not been conclusive. By this process, Pasteur curbs pébrine and saves many of the silk industry in the Cévennes. In 1878, at the Congrès international séricicole , Pasteur admitted that "if pébrine is overcome, flacherie still exerts its ravages". He attributed the persistence of flacherie to the fact that the farmers had not followed his advice. In 1884, Balbiani , who disregarded the theoretical value of Pasteur's work on silkworm diseases, acknowledged that his practical process had remedied the ravages of pébrine, but added that this result tended to be counterbalanced by the development of flacherie, which was less well known and more difficult to prevent. Despite Pasteur's success against pébrine, French sericulture had not been saved from damage. (See fr:Sériciculture in the French Wikipedia.)Arriving in Alès, Pasteur familiarized himself with pébrine and also with another disease of the silkworm, known earlier than pebrine: flacherie or dead-flat disease. Contrary, for example, to Quatrefages , who coined the new word pébrine , Pasteur made the mistake of believing that the two diseases were the same and even that most of the diseases of silkworms known up to that time were identical with each other and with pébrine. It was in letters of 30 April and 21 May 1867 to Dumas that he first made the distinction between pébrine and flacherie. He made another mistake: he began by denying the "parasitic" (microbial) nature of pébrine, which several scholars (notably Antoine Béchamp ) considered well established. Even a note published on 27 August 1866 by Balbiani , which Pasteur at first seemed to welcome favourably had no effect, at least immediately. "Pasteur is mistaken. He would only change his mind in the course of 1867". At a time where Pasteur had not yet understood the cause of the pébrine, he propagated an effective process to stop infections: a sample of chrysalises was chosen, they were crushed and the corpuscles were searched for in the crushed material; if the proportion of corpuscular pupae in the sample was very low, the chamber was considered good for reproduction. This method of sorting "seeds" (eggs) is close to a method that Osimo had proposed a few years earlier, but whose trials had not been conclusive. By this process, Pasteur curbs pébrine and saves many of the silk industry in the Cévennes. In 1878, at the Congrès international séricicole , Pasteur admitted that "if pébrine is overcome, flacherie still exerts its ravages". He attributed the persistence of flacherie to the fact that the farmers had not followed his advice. In 1884, Balbiani , who disregarded the theoretical value of Pasteur's work on silkworm diseases, acknowledged that his practical process had remedied the ravages of pébrine, but added that this result tended to be counterbalanced by the development of flacherie, which was less well known and more difficult to prevent. Despite Pasteur's success against pébrine, French sericulture had not been saved from damage. (See fr:Sériciculture in the French Wikipedia.)Pasteur's first work on vaccine development was on chicken cholera . He received the bacteria samples (later called Pasteurella multocida after him) from Henry Toussaint . He started the study in 1877, and by the next year, was able to maintain a stable culture using broths. After another year of continuous culturing, he found that the bacteria were less pathogenic. Some of his culture samples could no longer induce the disease in healthy chickens . In 1879, Pasteur, planning for holiday, instructed his assistant, Charles Chamberland to inoculate the chickens with fresh bacteria culture. Chamberland forgot and went on holiday himself. On his return, he injected the month-old cultures to healthy chickens. The chickens showed some symptoms of infection, but instead of the infections being fatal, as they usually were, the chickens recovered completely. Chamberland assumed an error had been made, and wanted to discard the apparently faulty culture, but Pasteur stopped him. Pasteur injected the freshly recovered chickens with fresh bacteria that normally would kill other chickens; the chickens no longer showed any sign of infection. It was clear to him that the weakened bacteria had caused the chickens to become immune to the disease. In December 1880, Pasteur presented his results to the French Academy of Sciences as " Sur les maladies virulentes et en particulier sur la maladie appelée vulgairement choléra des poules (On virulent diseases, and in particular on the disease commonly called chicken cholera)" and published it in the academy's journal ( Comptes-Rendus hebdomadaires des séances de l'Académie des Sciences ). He attributed that the bacteria were weakened by contact with oxygen. He explained that bacteria kept in sealed containers never lost their virulence, and only those exposed to air in culture media could be used as vaccine. Pasteur introduced the term "attenuation" for this weakening of virulence as he presented before the academy, saying: We can diminish the microbe's virulence by changing the mode of culturing. This is the crucial point of my subject. I ask the Academy not to criticize, for the time being, the confidence of my proceedings that permit me to determine the microbe's attenuation, in order to save the independence of my studies and to better assure their progress... [In conclusion] I would like to point out to the Academy two main consequences to the facts presented: the hope to culture all microbes and to find a vaccine for all infectious diseases that have repeatedly afflicted humanity, and are a major burden on agriculture and breeding of domestic animals. In fact, Pasteur's vaccine against chicken cholera was not regular in its effects and was a failure. In the 1870s, he applied this immunization method to anthrax , which affected cattle , and aroused interest in combating other diseases. Pasteur cultivated bacteria from the blood of animals infected with anthrax. When he inoculated animals with the bacteria, anthrax occurred, proving that the bacteria was the cause of the disease. Many cattle were dying of anthrax in "cursed fields". Pasteur was told that sheep that died from anthrax were buried in the field. Pasteur thought that earthworms might have brought the bacteria to the surface. He found anthrax bacteria in earthworms' excrement, showing that he was correct. He told the farmers not to bury dead animals in the fields. Pasteur had been trying to develop the anthrax vaccine since 1877, soon after Robert Koch's discovery of the bacterium. On 12 July 1880, Henri Bouley read before the French Academy of Sciences a report from Henry Toussaint , a veterinary surgeon , who was not member of the academy. Toussaint had developed anthrax vaccine by killing the bacilli by heating at 55 °C for 10  minutes. He tested on eight dogs and 11 sheep, half of which died after inoculation. It was not a great success. Upon hearing the news, Pasteur immediately wrote to the academy that he could not believe that dead vaccine would work and that Toussaint's claim "overturns all the ideas I had on viruses, vaccines, etc." Following Pasteur's criticism, Toussaint switched to carbolic acid to kill anthrax bacilli and tested the vaccine on sheep in August 1880. Pasteur thought that this type of killed vaccine should not work because he believed that attenuated bacteria used up nutrients that the bacteria needed to grow. He thought oxidizing bacteria made them less virulent. But Pasteur found that anthrax bacillus was not easily weakened by culturing in air as it formed spores – unlike chicken cholera bacillus. In early 1881, he discovered that growing anthrax bacilli at about 42 °C made them unable to produce spores, and he described this method in a speech to the French Academy of Sciences on 28 February. On 21 March, he announced successful vaccination of sheep. To this news, veterinarian Hippolyte Rossignol proposed that the Société d'agriculture de Melun organize an experiment to test Pasteur's vaccine. Pasteur signed agreement of the challenge on 28 April. A public experiment was conducted in May at Pouilly-le-Fort. 58 sheep, 2 goats and 10 cattle were used, half of which were given the vaccine on 5 and 17 May; while the other half was untreated. All the animals were injected with the fresh virulent culture of anthrax bacillus on 31 May. The official result was observed and analysed on 2 June in the presence of over 200 spectators. All cattle survived, vaccinated or not. Pasteur had bravely predicted: "I hypothesized that the six vaccinated cows would not become very ill, while the four unvaccinated cows would perish or at least become very ill." However, all vaccinated sheep and goats survived, while unvaccinated ones had died or were dying before the viewers. His report to the French Academy of Sciences on 13 June concludes: [By] looking at everything from the scientific point of view, the development of a vaccination against anthrax constitutes significant progress beyond the first vaccine developed by Jenner, since the latter had never been obtained experimentally. Pasteur did not directly disclose how he prepared the vaccines used at Pouilly-le-Fort. Although his report indicated it as a "live vaccine", his laboratory notebooks show that he actually used potassium dichromate -killed vaccine, as developed by Chamberland, quite similar to Toussaint's method. The notion of a weak form of a disease causing immunity to the virulent version was not new; this had been known for a long time for smallpox . Inoculation with smallpox ( variolation ) was known to result in a much less severe disease, and greatly reduced mortality, in comparison with the naturally acquired disease. Edward Jenner had also studied vaccination using cowpox ( vaccinia ) to give cross-immunity to smallpox in the late 1790s, and by the early 1800s vaccination had spread to most of Europe. The difference between smallpox vaccination and anthrax or chicken cholera vaccination was that the latter two disease organisms had been artificially weakened, so a naturally weak form of the disease organism did not need to be found. This discovery revolutionized work in infectious diseases, and Pasteur gave these artificially weakened diseases the generic name of " vaccines ", in honour of Jenner's discovery. In 1876, Robert Koch had shown that Bacillus anthracis caused anthrax. In his papers published between 1878 and 1880, Pasteur only mentioned Koch's work in a footnote. Koch met Pasteur at the Seventh International Medical Congress in 1881. A few months later, Koch wrote that Pasteur had used impure cultures and made errors. In 1882, Pasteur replied to Koch in a speech, to which Koch responded aggressively. Koch stated that Pasteur tested his vaccine on unsuitable animals and that Pasteur's research was not properly scientific. In 1882, Koch wrote "On the Anthrax Inoculation", in which he refuted several of Pasteur's conclusions about anthrax and criticized Pasteur for keeping his methods secret, jumping to conclusions, and being imprecise. In 1883, Pasteur wrote that he used cultures prepared in a similar way to his successful fermentation experiments and that Koch misinterpreted statistics and ignored Pasteur's work on silkworms. In 1882, Pasteur sent his assistant Louis Thuillier to southern France because of an epizootic of swine erysipelas . Thuillier identified the bacillus that caused the disease in March 1883. Pasteur and Thuillier increased the bacillus's virulence after passing it through pigeons. Then they passed the bacillus through rabbits, weakening it and obtaining a vaccine. Pasteur and Thuillier incorrectly described the bacterium as a figure-eight shape. Roux described the bacterium as stick-shaped in 1884. Pasteur produced the first vaccine for rabies by growing the virus in rabbits, and then weakening it by drying the affected nerve tissue. The rabies vaccine was initially created by Emile Roux , a French doctor and a colleague of Pasteur, who had produced a killed vaccine using this method. The vaccine had been tested in 50 dogs before its first human trial. This vaccine was used on 9-year-old Joseph Meister , on 6 July 1885, after the boy was badly mauled by a rabid dog. This was done at some personal risk for Pasteur, since he was not a licensed physician and could have faced prosecution for treating the boy. After consulting with physicians, he decided to go ahead with the treatment. Over 11 days, Meister received 13 inoculations, each inoculation using viruses that had been weakened for a shorter period of time. Three months later he examined Meister and found that he was in good health. Pasteur was hailed as a hero and the legal matter was not pursued. Analysis of his laboratory notebooks shows that Pasteur had treated two people before his vaccination of Meister. One survived but may not actually have had rabies, and the other died of rabies. Pasteur began treatment of Jean-Baptiste Jupille on 20 October 1885, and the treatment was successful. Later in 1885, people, including four children from the United States, went to Pasteur's laboratory to be inoculated. In 1886, he treated 350 people, of which only one developed rabies. The treatment's success laid the foundations for the manufacture of many other vaccines. The first of the Pasteur Institutes was also built on the basis of this achievement. In The Story of San Michele , Axel Munthe writes of some risks Pasteur undertook in the rabies vaccine research: Pasteur himself was absolutely fearless. Anxious to secure a sample of saliva straight from the jaws of a rabid dog, I once saw him with the glass tube held between his lips draw a few drops of the deadly saliva from the mouth of a rabid bull-dog, held on the table by two assistants, their hands protected by leather gloves. Because of his study in germs, Pasteur encouraged doctors to sanitize their hands and equipment before surgery. Prior to this, few doctors or their assistants practiced these procedures. Ignaz Semmelweis and Joseph Lister had earlier practiced hand sanitizing in medical contexts in the 1860s. Pasteur's first work on vaccine development was on chicken cholera . He received the bacteria samples (later called Pasteurella multocida after him) from Henry Toussaint . He started the study in 1877, and by the next year, was able to maintain a stable culture using broths. After another year of continuous culturing, he found that the bacteria were less pathogenic. Some of his culture samples could no longer induce the disease in healthy chickens . In 1879, Pasteur, planning for holiday, instructed his assistant, Charles Chamberland to inoculate the chickens with fresh bacteria culture. Chamberland forgot and went on holiday himself. On his return, he injected the month-old cultures to healthy chickens. The chickens showed some symptoms of infection, but instead of the infections being fatal, as they usually were, the chickens recovered completely. Chamberland assumed an error had been made, and wanted to discard the apparently faulty culture, but Pasteur stopped him. Pasteur injected the freshly recovered chickens with fresh bacteria that normally would kill other chickens; the chickens no longer showed any sign of infection. It was clear to him that the weakened bacteria had caused the chickens to become immune to the disease. In December 1880, Pasteur presented his results to the French Academy of Sciences as " Sur les maladies virulentes et en particulier sur la maladie appelée vulgairement choléra des poules (On virulent diseases, and in particular on the disease commonly called chicken cholera)" and published it in the academy's journal ( Comptes-Rendus hebdomadaires des séances de l'Académie des Sciences ). He attributed that the bacteria were weakened by contact with oxygen. He explained that bacteria kept in sealed containers never lost their virulence, and only those exposed to air in culture media could be used as vaccine. Pasteur introduced the term "attenuation" for this weakening of virulence as he presented before the academy, saying: We can diminish the microbe's virulence by changing the mode of culturing. This is the crucial point of my subject. I ask the Academy not to criticize, for the time being, the confidence of my proceedings that permit me to determine the microbe's attenuation, in order to save the independence of my studies and to better assure their progress... [In conclusion] I would like to point out to the Academy two main consequences to the facts presented: the hope to culture all microbes and to find a vaccine for all infectious diseases that have repeatedly afflicted humanity, and are a major burden on agriculture and breeding of domestic animals. In fact, Pasteur's vaccine against chicken cholera was not regular in its effects and was a failure. In the 1870s, he applied this immunization method to anthrax , which affected cattle , and aroused interest in combating other diseases. Pasteur cultivated bacteria from the blood of animals infected with anthrax. When he inoculated animals with the bacteria, anthrax occurred, proving that the bacteria was the cause of the disease. Many cattle were dying of anthrax in "cursed fields". Pasteur was told that sheep that died from anthrax were buried in the field. Pasteur thought that earthworms might have brought the bacteria to the surface. He found anthrax bacteria in earthworms' excrement, showing that he was correct. He told the farmers not to bury dead animals in the fields. Pasteur had been trying to develop the anthrax vaccine since 1877, soon after Robert Koch's discovery of the bacterium. On 12 July 1880, Henri Bouley read before the French Academy of Sciences a report from Henry Toussaint , a veterinary surgeon , who was not member of the academy. Toussaint had developed anthrax vaccine by killing the bacilli by heating at 55 °C for 10  minutes. He tested on eight dogs and 11 sheep, half of which died after inoculation. It was not a great success. Upon hearing the news, Pasteur immediately wrote to the academy that he could not believe that dead vaccine would work and that Toussaint's claim "overturns all the ideas I had on viruses, vaccines, etc." Following Pasteur's criticism, Toussaint switched to carbolic acid to kill anthrax bacilli and tested the vaccine on sheep in August 1880. Pasteur thought that this type of killed vaccine should not work because he believed that attenuated bacteria used up nutrients that the bacteria needed to grow. He thought oxidizing bacteria made them less virulent. But Pasteur found that anthrax bacillus was not easily weakened by culturing in air as it formed spores – unlike chicken cholera bacillus. In early 1881, he discovered that growing anthrax bacilli at about 42 °C made them unable to produce spores, and he described this method in a speech to the French Academy of Sciences on 28 February. On 21 March, he announced successful vaccination of sheep. To this news, veterinarian Hippolyte Rossignol proposed that the Société d'agriculture de Melun organize an experiment to test Pasteur's vaccine. Pasteur signed agreement of the challenge on 28 April. A public experiment was conducted in May at Pouilly-le-Fort. 58 sheep, 2 goats and 10 cattle were used, half of which were given the vaccine on 5 and 17 May; while the other half was untreated. All the animals were injected with the fresh virulent culture of anthrax bacillus on 31 May. The official result was observed and analysed on 2 June in the presence of over 200 spectators. All cattle survived, vaccinated or not. Pasteur had bravely predicted: "I hypothesized that the six vaccinated cows would not become very ill, while the four unvaccinated cows would perish or at least become very ill." However, all vaccinated sheep and goats survived, while unvaccinated ones had died or were dying before the viewers. His report to the French Academy of Sciences on 13 June concludes: [By] looking at everything from the scientific point of view, the development of a vaccination against anthrax constitutes significant progress beyond the first vaccine developed by Jenner, since the latter had never been obtained experimentally. Pasteur did not directly disclose how he prepared the vaccines used at Pouilly-le-Fort. Although his report indicated it as a "live vaccine", his laboratory notebooks show that he actually used potassium dichromate -killed vaccine, as developed by Chamberland, quite similar to Toussaint's method. The notion of a weak form of a disease causing immunity to the virulent version was not new; this had been known for a long time for smallpox . Inoculation with smallpox ( variolation ) was known to result in a much less severe disease, and greatly reduced mortality, in comparison with the naturally acquired disease. Edward Jenner had also studied vaccination using cowpox ( vaccinia ) to give cross-immunity to smallpox in the late 1790s, and by the early 1800s vaccination had spread to most of Europe. The difference between smallpox vaccination and anthrax or chicken cholera vaccination was that the latter two disease organisms had been artificially weakened, so a naturally weak form of the disease organism did not need to be found. This discovery revolutionized work in infectious diseases, and Pasteur gave these artificially weakened diseases the generic name of " vaccines ", in honour of Jenner's discovery. In 1876, Robert Koch had shown that Bacillus anthracis caused anthrax. In his papers published between 1878 and 1880, Pasteur only mentioned Koch's work in a footnote. Koch met Pasteur at the Seventh International Medical Congress in 1881. A few months later, Koch wrote that Pasteur had used impure cultures and made errors. In 1882, Pasteur replied to Koch in a speech, to which Koch responded aggressively. Koch stated that Pasteur tested his vaccine on unsuitable animals and that Pasteur's research was not properly scientific. In 1882, Koch wrote "On the Anthrax Inoculation", in which he refuted several of Pasteur's conclusions about anthrax and criticized Pasteur for keeping his methods secret, jumping to conclusions, and being imprecise. In 1883, Pasteur wrote that he used cultures prepared in a similar way to his successful fermentation experiments and that Koch misinterpreted statistics and ignored Pasteur's work on silkworms. In 1882, Pasteur sent his assistant Louis Thuillier to southern France because of an epizootic of swine erysipelas . Thuillier identified the bacillus that caused the disease in March 1883. Pasteur and Thuillier increased the bacillus's virulence after passing it through pigeons. Then they passed the bacillus through rabbits, weakening it and obtaining a vaccine. Pasteur and Thuillier incorrectly described the bacterium as a figure-eight shape. Roux described the bacterium as stick-shaped in 1884. Pasteur produced the first vaccine for rabies by growing the virus in rabbits, and then weakening it by drying the affected nerve tissue. The rabies vaccine was initially created by Emile Roux , a French doctor and a colleague of Pasteur, who had produced a killed vaccine using this method. The vaccine had been tested in 50 dogs before its first human trial. This vaccine was used on 9-year-old Joseph Meister , on 6 July 1885, after the boy was badly mauled by a rabid dog. This was done at some personal risk for Pasteur, since he was not a licensed physician and could have faced prosecution for treating the boy. After consulting with physicians, he decided to go ahead with the treatment. Over 11 days, Meister received 13 inoculations, each inoculation using viruses that had been weakened for a shorter period of time. Three months later he examined Meister and found that he was in good health. Pasteur was hailed as a hero and the legal matter was not pursued. Analysis of his laboratory notebooks shows that Pasteur had treated two people before his vaccination of Meister. One survived but may not actually have had rabies, and the other died of rabies. Pasteur began treatment of Jean-Baptiste Jupille on 20 October 1885, and the treatment was successful. Later in 1885, people, including four children from the United States, went to Pasteur's laboratory to be inoculated. In 1886, he treated 350 people, of which only one developed rabies. The treatment's success laid the foundations for the manufacture of many other vaccines. The first of the Pasteur Institutes was also built on the basis of this achievement. In The Story of San Michele , Axel Munthe writes of some risks Pasteur undertook in the rabies vaccine research: Pasteur himself was absolutely fearless. Anxious to secure a sample of saliva straight from the jaws of a rabid dog, I once saw him with the glass tube held between his lips draw a few drops of the deadly saliva from the mouth of a rabid bull-dog, held on the table by two assistants, their hands protected by leather gloves. Because of his study in germs, Pasteur encouraged doctors to sanitize their hands and equipment before surgery. Prior to this, few doctors or their assistants practiced these procedures. Ignaz Semmelweis and Joseph Lister had earlier practiced hand sanitizing in medical contexts in the 1860s. A French national hero at age 55, in 1878 Pasteur discreetly told his family to never reveal his laboratory notebooks to anyone. His family obeyed, and all his documents were held and inherited in secrecy. Finally, in 1964 Pasteur's grandson and last surviving male descendant, Pasteur Vallery-Radot, donated the papers to the French national library . Yet the papers were restricted for historical studies until the death of Vallery-Radot in 1971. The documents were given a catalogue number only in 1985. In 1995, the centennial of the death of Louis Pasteur, a historian of science Gerald L. Geison published an analysis of Pasteur's private notebooks in his The Private Science of Louis Pasteur , and declared that Pasteur had given several misleading accounts and played deceptions in his most important discoveries. Max Perutz published a defense of Pasteur in The New York Review of Books . Based on further examinations of Pasteur's documents, French immunologist Patrice Debré concluded in his book Louis Pasteur (1998) that, in spite of his genius, Pasteur had some faults. A book review states that Debré "sometimes finds him unfair, combative, arrogant, unattractive in attitude, inflexible and even dogmatic". Scientists before Pasteur had studied fermentation. In the 1830s, Charles Cagniard-Latour , Friedrich Traugott Kützing and Theodor Schwann used microscopes to study yeasts and concluded that yeasts were living organisms. In 1839, Justus von Liebig , Friedrich Wöhler and Jöns Jacob Berzelius stated that yeast was not an organism and was produced when air acted on plant juice. In 1855, Antoine Béchamp , Professor of Chemistry at the University of Montpellier , conducted experiments with sucrose solutions and concluded that water was the factor for fermentation. He changed his conclusion in 1858, stating that fermentation was directly related to the growth of moulds, which required air for growth. He regarded himself as the first to show the role of microorganisms in fermentation. Pasteur started his experiments in 1857 and published his findings in 1858 (April issue of Comptes Rendus Chimie , Béchamp's paper appeared in January issue). Béchamp noted that Pasteur did not bring any novel idea or experiments. On the other hand, Béchamp was probably aware of Pasteur's 1857 preliminary works. With both scientists claiming priority on the discovery, a dispute, extending to several areas, lasted throughout their lives. However, Béchamp was on the losing side, as the BMJ obituary remarked: His name was "associated with bygone controversies as to priority which it would be unprofitable to recall". Béchamp proposed the incorrect theory of microzymes . According to K. L. Manchester, anti-vivisectionists and proponents of alternative medicine promoted Béchamp and microzymes, unjustifiably claiming that Pasteur plagiarized Béchamp. Pasteur thought that succinic acid inverted sucrose. In 1860, Marcellin Berthelot isolated invertase and showed that succinic acid did not invert sucrose. Pasteur believed that fermentation was only due to living cells. He and Berthelot engaged in a long argument subject of vitalism, in which Berthelot was vehemently opposed to any idea of vitalism. Hans Buchner discovered that zymase (not an enzyme, but a mixture of enzymes) catalyzed fermentation, showing that fermentation was catalyzed by enzymes within cells. Eduard Buchner also discovered that fermentation could take place outside living cells. Pasteur publicly claimed his success in developing the anthrax vaccine in 1881. However, his admirer-turned-rival Henry Toussaint was the one who developed the first vaccine. Toussaint isolated the bacteria that caused chicken cholera (later named Pasteurella in honour of Pasteur) in 1879 and gave samples to Pasteur who used them for his own works. On 12 July 1880, Toussaint presented his successful result to the French Academy of Sciences, using an attenuated vaccine against anthrax in dogs and sheep. Pasteur on grounds of jealousy contested the discovery by publicly displaying his vaccination method at Pouilly-le-Fort on 5 May 1881. Pasteur then gave a misleading account of the preparation of the anthrax vaccine used in the experiment. He claimed that he made a "live vaccine", but used potassium dichromate to inactivate anthrax spores, a method similar to Toussaint's. The promotional experiment was a success and helped Pasteur sell his products, getting the benefits and glory. Pasteur's experiments are often cited as against medical ethics , especially on his vaccination of Meister. He did not have any experience in medical practice, and more importantly, lacked a medical license . This is often cited as a serious threat to his professional and personal reputation. His closest partner Émile Roux , who had medical qualifications, refused to participate in the clinical trial , likely because he considered it unjust. However, Pasteur executed vaccination of the boy under the close watch of practising physicians Jacques-Joseph Grancher , head of the Paris Children's Hospital's paediatric clinic, and Alfred Vulpian , a member of the Commission on Rabies. He was not allowed to hold the syringe, although the inoculations were entirely under his supervision. It was Grancher who was responsible for the injections, and he defended Pasteur before the French National Academy of Medicine in the issue. Pasteur has also been criticized for keeping secrecy of his procedure and not giving proper pre-clinical trials on animals. Pasteur stated that he kept his procedure secret in order to control its quality. He later disclosed his procedures to a small group of scientists. Pasteur wrote that he had successfully vaccinated 50 rabid dogs before using it on Meister. According to Geison, Pasteur's laboratory notebooks show that he had vaccinated only 11 dogs. Meister never showed any symptoms of rabies, but the vaccination has not been proved to be the reason. One source estimates the probability of Meister contracting rabies at 10%. Scientists before Pasteur had studied fermentation. In the 1830s, Charles Cagniard-Latour , Friedrich Traugott Kützing and Theodor Schwann used microscopes to study yeasts and concluded that yeasts were living organisms. In 1839, Justus von Liebig , Friedrich Wöhler and Jöns Jacob Berzelius stated that yeast was not an organism and was produced when air acted on plant juice. In 1855, Antoine Béchamp , Professor of Chemistry at the University of Montpellier , conducted experiments with sucrose solutions and concluded that water was the factor for fermentation. He changed his conclusion in 1858, stating that fermentation was directly related to the growth of moulds, which required air for growth. He regarded himself as the first to show the role of microorganisms in fermentation. Pasteur started his experiments in 1857 and published his findings in 1858 (April issue of Comptes Rendus Chimie , Béchamp's paper appeared in January issue). Béchamp noted that Pasteur did not bring any novel idea or experiments. On the other hand, Béchamp was probably aware of Pasteur's 1857 preliminary works. With both scientists claiming priority on the discovery, a dispute, extending to several areas, lasted throughout their lives. However, Béchamp was on the losing side, as the BMJ obituary remarked: His name was "associated with bygone controversies as to priority which it would be unprofitable to recall". Béchamp proposed the incorrect theory of microzymes . According to K. L. Manchester, anti-vivisectionists and proponents of alternative medicine promoted Béchamp and microzymes, unjustifiably claiming that Pasteur plagiarized Béchamp. Pasteur thought that succinic acid inverted sucrose. In 1860, Marcellin Berthelot isolated invertase and showed that succinic acid did not invert sucrose. Pasteur believed that fermentation was only due to living cells. He and Berthelot engaged in a long argument subject of vitalism, in which Berthelot was vehemently opposed to any idea of vitalism. Hans Buchner discovered that zymase (not an enzyme, but a mixture of enzymes) catalyzed fermentation, showing that fermentation was catalyzed by enzymes within cells. Eduard Buchner also discovered that fermentation could take place outside living cells. Pasteur publicly claimed his success in developing the anthrax vaccine in 1881. However, his admirer-turned-rival Henry Toussaint was the one who developed the first vaccine. Toussaint isolated the bacteria that caused chicken cholera (later named Pasteurella in honour of Pasteur) in 1879 and gave samples to Pasteur who used them for his own works. On 12 July 1880, Toussaint presented his successful result to the French Academy of Sciences, using an attenuated vaccine against anthrax in dogs and sheep. Pasteur on grounds of jealousy contested the discovery by publicly displaying his vaccination method at Pouilly-le-Fort on 5 May 1881. Pasteur then gave a misleading account of the preparation of the anthrax vaccine used in the experiment. He claimed that he made a "live vaccine", but used potassium dichromate to inactivate anthrax spores, a method similar to Toussaint's. The promotional experiment was a success and helped Pasteur sell his products, getting the benefits and glory. Pasteur's experiments are often cited as against medical ethics , especially on his vaccination of Meister. He did not have any experience in medical practice, and more importantly, lacked a medical license . This is often cited as a serious threat to his professional and personal reputation. His closest partner Émile Roux , who had medical qualifications, refused to participate in the clinical trial , likely because he considered it unjust. However, Pasteur executed vaccination of the boy under the close watch of practising physicians Jacques-Joseph Grancher , head of the Paris Children's Hospital's paediatric clinic, and Alfred Vulpian , a member of the Commission on Rabies. He was not allowed to hold the syringe, although the inoculations were entirely under his supervision. It was Grancher who was responsible for the injections, and he defended Pasteur before the French National Academy of Medicine in the issue. Pasteur has also been criticized for keeping secrecy of his procedure and not giving proper pre-clinical trials on animals. Pasteur stated that he kept his procedure secret in order to control its quality. He later disclosed his procedures to a small group of scientists. Pasteur wrote that he had successfully vaccinated 50 rabid dogs before using it on Meister. According to Geison, Pasteur's laboratory notebooks show that he had vaccinated only 11 dogs. Meister never showed any symptoms of rabies, but the vaccination has not been proved to be the reason. One source estimates the probability of Meister contracting rabies at 10%. Pasteur was awarded 1,500 francs in 1853 by the Pharmaceutical Society for the synthesis of racemic acid . In 1856 the Royal Society of London presented him the Rumford Medal for his discovery of the nature of racemic acid and its relations to polarized light, and the Copley Medal in 1874 for his work on fermentation. He was elected a Foreign Member of the Royal Society (ForMemRS) in 1869 . The French Academy of Sciences awarded Pasteur the 1859 Montyon Prize for experimental physiology in 1860, and the Jecker Prize in 1861 and the Alhumbert Prize in 1862 for his experimental refutation of spontaneous generation. Though he lost elections in 1857 and 1861 for membership to the French Academy of Sciences, he won the 1862 election for membership to the mineralogy section. He was elected to permanent secretary of the physical science section of the academy in 1887 and held the position until 1889. In 1873, Pasteur was elected to the Académie Nationale de Médecine and was made the commander in the Brazilian Order of the Rose . In 1881 he was elected to a seat at the Académie française left vacant by Émile Littré . Pasteur received the Albert Medal from the Royal Society of Arts in 1882. In 1883 he became foreign member of the Royal Netherlands Academy of Arts and Sciences . In 1885, he was elected as a member to the American Philosophical Society . On 8 June 1886, the Ottoman Sultan Abdul Hamid II awarded Pasteur with the Order of the Medjidie (I Class) and 10000 Ottoman liras. He was awarded the Cameron Prize for Therapeutics of the University of Edinburgh in 1889. Pasteur won the Leeuwenhoek Medal from the Royal Netherlands Academy of Arts and Sciences for his contributions to microbiology in 1895. Pasteur was made a Chevalier of the Legion of Honour in 1853, promoted to Officer in 1863, to Commander in 1868, to Grand Officer in 1878 and made a Grand Cross of the Legion of Honor in 1881. In many localities worldwide, streets are named in his honor. For example, in the US: Palo Alto and Irvine, California , Boston and Polk, Florida, adjacent to the University of Texas Health Science Center at San Antonio ; Jonquière, Québec; San Salvador de Jujuy and Buenos Aires ( Argentina ), Great Yarmouth in Norfolk, in the United Kingdom, Jericho and Wulguru in Queensland, Australia; Phnom Penh in Cambodia; Ho Chi Minh City and Da Nang , Vietnam; Batna in Algeria ; Bandung in Indonesia, Tehran in Iran, near the central campus of the Warsaw University in Warsaw , Poland; adjacent to the Odesa State Medical University in Odesa , Ukraine; Milan in Italy and Bucharest , Cluj-Napoca and Timișoara in Romania. The Avenue Pasteur in Saigon, Vietnam, is one of the few streets in that city to retain its French name. Avenue Louis Pasteur in the Longwood Medical and Academic Area in Boston was named in his honor in the French manner with "Avenue" preceding the name of the dedicatee. Both the Institut Pasteur and Université Louis Pasteur were named after Pasteur. The schools Lycée Pasteur in Neuilly-sur-Seine , France, and Lycée Louis Pasteur in Calgary, Alberta , Canada, are named after him. In South Africa, the Louis Pasteur Private Hospital in Pretoria , and Life Louis Pasteur Private Hospital, Bloemfontein , are named after him. Louis Pasteur University Hospital in Košice , Slovakia is also named after Pasteur. A statue of Pasteur is erected at San Rafael High School in San Rafael, California . A bronze bust of him resides on the French Campus of Kaiser Permanente 's San Francisco Medical Center in San Francisco . The sculpture was designed by Harriet G. Moore and cast in 1984 by Artworks Foundry. The UNESCO/Institut Pasteur Medal was created on the centenary of Pasteur's death, and is given every two years in his name, "in recognition of outstanding research contributing to a beneficial impact on human health". The French Academician Henri Mondor stated: " Louis Pasteur was neither a physician nor a surgeon, but no one has done as much for medicine and surgery as he has ." After developing the rabies vaccine, Pasteur proposed an institute for the vaccine. In 1887, fundraising for the Pasteur Institute began, with donations from many countries. The official statute was registered in 1887, stating that the institute's purposes were "the treatment of rabies according to the method developed by M. Pasteur" and "the study of virulent and contagious diseases". The institute was inaugurated on 14 November 1888. He brought together scientists with various specialties. The first five departments were directed by two graduates of the École Normale Supérieure : Émile Duclaux (general microbiology research) and Charles Chamberland (microbe research applied to hygiene ), as well as a biologist, Élie Metchnikoff (morphological microbe research) and two physicians , Jacques-Joseph Grancher ( rabies ) and Émile Roux (technical microbe research). One year after the inauguration of the institute, Roux set up the first course of microbiology ever taught in the world, then entitled Cours de Microbie Technique (Course of microbe research techniques). Since 1891 the Pasteur Institute had been extended to different countries, and currently there are 32 institutes in 29 countries in various parts of the world. In many localities worldwide, streets are named in his honor. For example, in the US: Palo Alto and Irvine, California , Boston and Polk, Florida, adjacent to the University of Texas Health Science Center at San Antonio ; Jonquière, Québec; San Salvador de Jujuy and Buenos Aires ( Argentina ), Great Yarmouth in Norfolk, in the United Kingdom, Jericho and Wulguru in Queensland, Australia; Phnom Penh in Cambodia; Ho Chi Minh City and Da Nang , Vietnam; Batna in Algeria ; Bandung in Indonesia, Tehran in Iran, near the central campus of the Warsaw University in Warsaw , Poland; adjacent to the Odesa State Medical University in Odesa , Ukraine; Milan in Italy and Bucharest , Cluj-Napoca and Timișoara in Romania. The Avenue Pasteur in Saigon, Vietnam, is one of the few streets in that city to retain its French name. Avenue Louis Pasteur in the Longwood Medical and Academic Area in Boston was named in his honor in the French manner with "Avenue" preceding the name of the dedicatee. Both the Institut Pasteur and Université Louis Pasteur were named after Pasteur. The schools Lycée Pasteur in Neuilly-sur-Seine , France, and Lycée Louis Pasteur in Calgary, Alberta , Canada, are named after him. In South Africa, the Louis Pasteur Private Hospital in Pretoria , and Life Louis Pasteur Private Hospital, Bloemfontein , are named after him. Louis Pasteur University Hospital in Košice , Slovakia is also named after Pasteur. A statue of Pasteur is erected at San Rafael High School in San Rafael, California . A bronze bust of him resides on the French Campus of Kaiser Permanente 's San Francisco Medical Center in San Francisco . The sculpture was designed by Harriet G. Moore and cast in 1984 by Artworks Foundry. The UNESCO/Institut Pasteur Medal was created on the centenary of Pasteur's death, and is given every two years in his name, "in recognition of outstanding research contributing to a beneficial impact on human health". The French Academician Henri Mondor stated: " Louis Pasteur was neither a physician nor a surgeon, but no one has done as much for medicine and surgery as he has ." After developing the rabies vaccine, Pasteur proposed an institute for the vaccine. In 1887, fundraising for the Pasteur Institute began, with donations from many countries. The official statute was registered in 1887, stating that the institute's purposes were "the treatment of rabies according to the method developed by M. Pasteur" and "the study of virulent and contagious diseases". The institute was inaugurated on 14 November 1888. He brought together scientists with various specialties. The first five departments were directed by two graduates of the École Normale Supérieure : Émile Duclaux (general microbiology research) and Charles Chamberland (microbe research applied to hygiene ), as well as a biologist, Élie Metchnikoff (morphological microbe research) and two physicians , Jacques-Joseph Grancher ( rabies ) and Émile Roux (technical microbe research). One year after the inauguration of the institute, Roux set up the first course of microbiology ever taught in the world, then entitled Cours de Microbie Technique (Course of microbe research techniques). Since 1891 the Pasteur Institute had been extended to different countries, and currently there are 32 institutes in 29 countries in various parts of the world. Pasteur married Marie Pasteur (née Laurent) in 1849. She was the daughter of the rector of the University of Strasbourg, and was Pasteur's scientific assistant. They had five children together, three of whom died as children. Their eldest daughter, Jeanne, was born in 1850. She died from typhoid fever , aged 9, whilst at the boarding school Arbois in 1859. In 1865, 2-year-old Camille died of a liver tumour. Shortly after they decided to bring Cécile home from boarding school, but she too died of typhoid fever on 23 May 1866 at the age of 12. Only Jean Baptiste (b. 1851) and Marie Louise (b. 1858) survived to adulthood. Jean Baptiste would be a soldier in the Franco-Prussian War between France and Prussia . His grandson, Louis Pasteur Vallery-Radot , wrote that Pasteur had kept from his Catholic background only a spiritualism without religious practice. However, Catholic observers often said that Pasteur remained an ardent Christian throughout his whole life, and his son-in-law wrote, in a biography of him: Absolute faith in God and in Eternity, and a conviction that the power for good given to us in this world will be continued beyond it, were feelings which pervaded his whole life; the virtues of the gospel had ever been present to him. Full of respect for the form of religion which had been that of his forefathers, he came simply to it and naturally for spiritual help in these last weeks of his life. The Literary Digest of 18 October 1902 gives this statement from Pasteur that he prayed while he worked: Posterity will one day laugh at the foolishness of modern materialistic philosophers. The more I study nature, the more I stand amazed at the work of the Creator. I pray while I am engaged at my work in the laboratory. Maurice Vallery-Radot, grandson of the brother of the son-in-law of Pasteur and outspoken Catholic, also holds that Pasteur fundamentally remained Catholic. According to both Pasteur Vallery-Radot and Maurice Vallery-Radot, the following well-known quotation attributed to Pasteur is apocryphal: "The more I know, the more nearly is my faith that of the Breton peasant. Could I but know all I would have the faith of a Breton peasant's wife". According to Maurice Vallery-Radot, the false quotation appeared for the first time shortly after the death of Pasteur. However, despite his belief in God, it has been said that his views were that of a freethinker rather than a Catholic, a spiritual more than a religious man. He was also against mixing science with religion. In 1868, Pasteur suffered a severe brain stroke that paralysed the left side of his body, but he recovered. A stroke or uremia in 1894 severely impaired his health. Failing to fully recover, he died on 28 September 1895, near Paris. He was given a state funeral and was buried in the Cathedral of Notre Dame , but his remains were reinterred in the Pasteur Institute in Paris, in a vault covered in depictions of his accomplishments in Byzantine mosaics . His grandson, Louis Pasteur Vallery-Radot , wrote that Pasteur had kept from his Catholic background only a spiritualism without religious practice. However, Catholic observers often said that Pasteur remained an ardent Christian throughout his whole life, and his son-in-law wrote, in a biography of him: Absolute faith in God and in Eternity, and a conviction that the power for good given to us in this world will be continued beyond it, were feelings which pervaded his whole life; the virtues of the gospel had ever been present to him. Full of respect for the form of religion which had been that of his forefathers, he came simply to it and naturally for spiritual help in these last weeks of his life. The Literary Digest of 18 October 1902 gives this statement from Pasteur that he prayed while he worked: Posterity will one day laugh at the foolishness of modern materialistic philosophers. The more I study nature, the more I stand amazed at the work of the Creator. I pray while I am engaged at my work in the laboratory. Maurice Vallery-Radot, grandson of the brother of the son-in-law of Pasteur and outspoken Catholic, also holds that Pasteur fundamentally remained Catholic. According to both Pasteur Vallery-Radot and Maurice Vallery-Radot, the following well-known quotation attributed to Pasteur is apocryphal: "The more I know, the more nearly is my faith that of the Breton peasant. Could I but know all I would have the faith of a Breton peasant's wife". According to Maurice Vallery-Radot, the false quotation appeared for the first time shortly after the death of Pasteur. However, despite his belief in God, it has been said that his views were that of a freethinker rather than a Catholic, a spiritual more than a religious man. He was also against mixing science with religion. In 1868, Pasteur suffered a severe brain stroke that paralysed the left side of his body, but he recovered. A stroke or uremia in 1894 severely impaired his health. Failing to fully recover, he died on 28 September 1895, near Paris. He was given a state funeral and was buried in the Cathedral of Notre Dame , but his remains were reinterred in the Pasteur Institute in Paris, in a vault covered in depictions of his accomplishments in Byzantine mosaics . Pasteur's principal published works are:

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Infection

An infection is the invasion of tissues by pathogens , their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease , also known as a transmissible disease or communicable disease , is an illness resulting from an infection. Infections can be caused by a wide range of pathogens , most prominently bacteria and viruses . Hosts can fight infections using their immune systems . Mammalian hosts react to infections with an innate response, often involving inflammation , followed by an adaptive response. Specific medications used to treat infections include antibiotics , antivirals , antifungals , antiprotozoals , and antihelminthics . Infectious diseases resulted in 9.2 million deaths in 2013 (about 17% of all deaths). The branch of medicine that focuses on infections is referred to as infectious diseases . Infections are caused by infectious agents ( pathogens ) including:The signs and symptoms of an infection depend on the type of disease. Some signs of infection affect the whole body generally, such as fatigue , loss of appetite, weight loss, fevers , night sweats, chills, aches and pains. Others are specific to individual body parts, such as skin rashes , coughing , or a runny nose . In certain cases, infectious diseases may be asymptomatic for much or even all of their course in a given host. In the latter case, the disease may only be defined as a "disease" (which by definition means an illness) in hosts who secondarily become ill after contact with an asymptomatic carrier . An infection is not synonymous with an infectious disease, as some infections do not cause illness in a host. As bacterial and viral infections can both cause the same kinds of symptoms, it can be difficult to distinguish which is the cause of a specific infection. Distinguishing the two is important, since viral infections cannot be cured by antibiotics whereas bacterial infections can. As bacterial and viral infections can both cause the same kinds of symptoms, it can be difficult to distinguish which is the cause of a specific infection. Distinguishing the two is important, since viral infections cannot be cured by antibiotics whereas bacterial infections can. There is a general chain of events that applies to infections, sometimes called the chain of infection or transmission chain . The chain of events involves several steps – which include the infectious agent, reservoir, entering a susceptible host, exit and transmission to new hosts. Each of the links must be present in a chronological order for an infection to develop. Understanding these steps helps health care workers target the infection and prevent it from occurring in the first place. Infection begins when an organism successfully enters the body, grows and multiplies. This is referred to as colonization. Most humans are not easily infected. Those with compromised or weakened immune systems have an increased susceptibility to chronic or persistent infections. Individuals who have a suppressed immune system are particularly susceptible to opportunistic infections . Entrance to the host at host–pathogen interface , generally occurs through the mucosa in orifices like the oral cavity , nose, eyes, genitalia, anus, or the microbe can enter through open wounds. While a few organisms can grow at the initial site of entry, many migrate and cause systemic infection in different organs. Some pathogens grow within the host cells (intracellular) whereas others grow freely in bodily fluids. Wound colonization refers to non-replicating microorganisms within the wound, while in infected wounds, replicating organisms exist and tissue is injured. All multicellular organisms are colonized to some degree by extrinsic organisms, and the vast majority of these exist in either a mutualistic or commensal relationship with the host. An example of the former is the anaerobic bacteria species, which colonizes the mammalian colon , and an example of the latter are the various species of staphylococcus that exist on human skin . Neither of these colonizations are considered infections. The difference between an infection and a colonization is often only a matter of circumstance. Non-pathogenic organisms can become pathogenic given specific conditions, and even the most virulent organism requires certain circumstances to cause a compromising infection. Some colonizing bacteria, such as Corynebacteria sp. and Viridans streptococci , prevent the adhesion and colonization of pathogenic bacteria and thus have a symbiotic relationship with the host, preventing infection and speeding wound healing . The variables involved in the outcome of a host becoming inoculated by a pathogen and the ultimate outcome include: As an example, several staphylococcal species remain harmless on the skin, but, when present in a normally sterile space, such as in the capsule of a joint or the peritoneum , multiply without resistance and cause harm. An interesting fact that gas chromatography–mass spectrometry , 16S ribosomal RNA analysis, omics , and other advanced technologies have made more apparent to humans in recent decades is that microbial colonization is very common even in environments that humans think of as being nearly sterile . Because it is normal to have bacterial colonization, it is difficult to know which chronic wounds can be classified as infected and how much risk of progression exists. Despite the huge number of wounds seen in clinical practice, there are limited quality data for evaluated symptoms and signs. A review of chronic wounds in the Journal of the American Medical Association 's "Rational Clinical Examination Series" quantified the importance of increased pain as an indicator of infection. The review showed that the most useful finding is an increase in the level of pain [likelihood ratio (LR) range, 11–20] makes infection much more likely, but the absence of pain (negative likelihood ratio range, 0.64–0.88) does not rule out infection (summary LR 0.64–0.88). Disease can arise if the host's protective immune mechanisms are compromised and the organism inflicts damage on the host. Microorganisms can cause tissue damage by releasing a variety of toxins or destructive enzymes. For example, Clostridium tetani releases a toxin that paralyzes muscles, and staphylococcus releases toxins that produce shock and sepsis . Not all infectious agents cause disease in all hosts. For example, less than 5% of individuals infected with polio develop disease. On the other hand, some infectious agents are highly virulent. The prion causing mad cow disease and Creutzfeldt–Jakob disease invariably kills all animals and people that are infected. Persistent infections occur because the body is unable to clear the organism after the initial infection. Persistent infections are characterized by the continual presence of the infectious organism, often as latent infection with occasional recurrent relapses of active infection. There are some viruses that can maintain a persistent infection by infecting different cells of the body. Some viruses once acquired never leave the body. A typical example is the herpes virus, which tends to hide in nerves and become reactivated when specific circumstances arise. Persistent infections cause millions of deaths globally each year. Chronic infections by parasites account for a high morbidity and mortality in many underdeveloped countries. For infecting organisms to survive and repeat the infection cycle in other hosts, they (or their progeny) must leave an existing reservoir and cause infection elsewhere. Infection transmission can take place via many potential routes: The relationship between virulence versus transmissibility is complex; with studies have shown that there were no clear relationship between the two. There is still a small number of evidence that partially suggests a link between virulence and transmissibility. Infection begins when an organism successfully enters the body, grows and multiplies. This is referred to as colonization. Most humans are not easily infected. Those with compromised or weakened immune systems have an increased susceptibility to chronic or persistent infections. Individuals who have a suppressed immune system are particularly susceptible to opportunistic infections . Entrance to the host at host–pathogen interface , generally occurs through the mucosa in orifices like the oral cavity , nose, eyes, genitalia, anus, or the microbe can enter through open wounds. While a few organisms can grow at the initial site of entry, many migrate and cause systemic infection in different organs. Some pathogens grow within the host cells (intracellular) whereas others grow freely in bodily fluids. Wound colonization refers to non-replicating microorganisms within the wound, while in infected wounds, replicating organisms exist and tissue is injured. All multicellular organisms are colonized to some degree by extrinsic organisms, and the vast majority of these exist in either a mutualistic or commensal relationship with the host. An example of the former is the anaerobic bacteria species, which colonizes the mammalian colon , and an example of the latter are the various species of staphylococcus that exist on human skin . Neither of these colonizations are considered infections. The difference between an infection and a colonization is often only a matter of circumstance. Non-pathogenic organisms can become pathogenic given specific conditions, and even the most virulent organism requires certain circumstances to cause a compromising infection. Some colonizing bacteria, such as Corynebacteria sp. and Viridans streptococci , prevent the adhesion and colonization of pathogenic bacteria and thus have a symbiotic relationship with the host, preventing infection and speeding wound healing . The variables involved in the outcome of a host becoming inoculated by a pathogen and the ultimate outcome include: As an example, several staphylococcal species remain harmless on the skin, but, when present in a normally sterile space, such as in the capsule of a joint or the peritoneum , multiply without resistance and cause harm. An interesting fact that gas chromatography–mass spectrometry , 16S ribosomal RNA analysis, omics , and other advanced technologies have made more apparent to humans in recent decades is that microbial colonization is very common even in environments that humans think of as being nearly sterile . Because it is normal to have bacterial colonization, it is difficult to know which chronic wounds can be classified as infected and how much risk of progression exists. Despite the huge number of wounds seen in clinical practice, there are limited quality data for evaluated symptoms and signs. A review of chronic wounds in the Journal of the American Medical Association 's "Rational Clinical Examination Series" quantified the importance of increased pain as an indicator of infection. The review showed that the most useful finding is an increase in the level of pain [likelihood ratio (LR) range, 11–20] makes infection much more likely, but the absence of pain (negative likelihood ratio range, 0.64–0.88) does not rule out infection (summary LR 0.64–0.88). Disease can arise if the host's protective immune mechanisms are compromised and the organism inflicts damage on the host. Microorganisms can cause tissue damage by releasing a variety of toxins or destructive enzymes. For example, Clostridium tetani releases a toxin that paralyzes muscles, and staphylococcus releases toxins that produce shock and sepsis . Not all infectious agents cause disease in all hosts. For example, less than 5% of individuals infected with polio develop disease. On the other hand, some infectious agents are highly virulent. The prion causing mad cow disease and Creutzfeldt–Jakob disease invariably kills all animals and people that are infected. Persistent infections occur because the body is unable to clear the organism after the initial infection. Persistent infections are characterized by the continual presence of the infectious organism, often as latent infection with occasional recurrent relapses of active infection. There are some viruses that can maintain a persistent infection by infecting different cells of the body. Some viruses once acquired never leave the body. A typical example is the herpes virus, which tends to hide in nerves and become reactivated when specific circumstances arise. Persistent infections cause millions of deaths globally each year. Chronic infections by parasites account for a high morbidity and mortality in many underdeveloped countries. For infecting organisms to survive and repeat the infection cycle in other hosts, they (or their progeny) must leave an existing reservoir and cause infection elsewhere. Infection transmission can take place via many potential routes: The relationship between virulence versus transmissibility is complex; with studies have shown that there were no clear relationship between the two. There is still a small number of evidence that partially suggests a link between virulence and transmissibility. Diagnosis of infectious disease sometimes involves identifying an infectious agent either directly or indirectly. In practice most minor infectious diseases such as warts , cutaneous abscesses , respiratory system infections and diarrheal diseases are diagnosed by their clinical presentation and treated without knowledge of the specific causative agent. Conclusions about the cause of the disease are based upon the likelihood that a patient came in contact with a particular agent, the presence of a microbe in a community, and other epidemiological considerations. Given sufficient effort, all known infectious agents can be specifically identified. Diagnosis of infectious disease is nearly always initiated by medical history and physical examination. More detailed identification techniques involve the culture of infectious agents isolated from a patient. Culture allows identification of infectious organisms by examining their microscopic features, by detecting the presence of substances produced by pathogens, and by directly identifying an organism by its genotype. Many infectious organisms are identified without culture and microscopy. This is especially true for viruses, which cannot grow in culture. For some suspected pathogens, doctors may conduct tests that examine a patient's blood or other body fluids for antigens or antibodies that indicate presence of a specific pathogen that the doctor suspects. Other techniques (such as X-rays , CAT scans , PET scans or NMR ) are used to produce images of internal abnormalities resulting from the growth of an infectious agent. The images are useful in detection of, for example, a bone abscess or a spongiform encephalopathy produced by a prion . The benefits of identification, however, are often greatly outweighed by the cost, as often there is no specific treatment, the cause is obvious, or the outcome of an infection is likely to be benign . The diagnosis is aided by the presenting symptoms in any individual with an infectious disease, yet it usually needs additional diagnostic techniques to confirm the suspicion. Some signs are specifically characteristic and indicative of a disease and are called pathognomonic signs; but these are rare. Not all infections are symptomatic. In children the presence of cyanosis , rapid breathing, poor peripheral perfusion, or a petechial rash increases the risk of a serious infection by greater than 5 fold. Other important indicators include parental concern, clinical instinct, and temperature greater than 40 °C. Many diagnostic approaches depend on microbiological culture to isolate a pathogen from the appropriate clinical specimen. In a microbial culture, a growth medium is provided for a specific agent. A sample taken from potentially diseased tissue or fluid is then tested for the presence of an infectious agent able to grow within that medium. Many pathogenic bacteria are easily grown on nutrient agar , a form of solid medium that supplies carbohydrates and proteins necessary for growth, along with copious amounts of water. A single bacterium will grow into a visible mound on the surface of the plate called a colony , which may be separated from other colonies or melded together into a "lawn". The size, color, shape and form of a colony is characteristic of the bacterial species, its specific genetic makeup (its strain ), and the environment that supports its growth. Other ingredients are often added to the plate to aid in identification. Plates may contain substances that permit the growth of some bacteria and not others, or that change color in response to certain bacteria and not others. Bacteriological plates such as these are commonly used in the clinical identification of infectious bacterium. Microbial culture may also be used in the identification of viruses : the medium, in this case, being cells grown in culture that the virus can infect, and then alter or kill. In the case of viral identification, a region of dead cells results from viral growth, and is called a "plaque". Eukaryotic parasites may also be grown in culture as a means of identifying a particular agent. In the absence of suitable plate culture techniques, some microbes require culture within live animals. Bacteria such as Mycobacterium leprae and Treponema pallidum can be grown in animals, although serological and microscopic techniques make the use of live animals unnecessary. Viruses are also usually identified using alternatives to growth in culture or animals. Some viruses may be grown in embryonated eggs. Another useful identification method is Xenodiagnosis, or the use of a vector to support the growth of an infectious agent. Chagas disease is the most significant example, because it is difficult to directly demonstrate the presence of the causative agent, Trypanosoma cruzi in a patient, which therefore makes it difficult to definitively make a diagnosis. In this case, xenodiagnosis involves the use of the vector of the Chagas agent T. cruzi , an uninfected triatomine bug, which takes a blood meal from a person suspected of having been infected. The bug is later inspected for growth of T. cruzi within its gut. Another principal tool in the diagnosis of infectious disease is microscopy . Virtually all of the culture techniques discussed above rely, at some point, on microscopic examination for definitive identification of the infectious agent. Microscopy may be carried out with simple instruments, such as the compound light microscope , or with instruments as complex as an electron microscope . Samples obtained from patients may be viewed directly under the light microscope, and can often rapidly lead to identification. Microscopy is often also used in conjunction with biochemical staining techniques, and can be made exquisitely specific when used in combination with antibody based techniques. For example, the use of antibodies made artificially fluorescent (fluorescently labeled antibodies) can be directed to bind to and identify a specific antigens present on a pathogen. A fluorescence microscope is then used to detect fluorescently labeled antibodies bound to internalized antigens within clinical samples or cultured cells. This technique is especially useful in the diagnosis of viral diseases, where the light microscope is incapable of identifying a virus directly. Other microscopic procedures may also aid in identifying infectious agents. Almost all cells readily stain with a number of basic dyes due to the electrostatic attraction between negatively charged cellular molecules and the positive charge on the dye. A cell is normally transparent under a microscope, and using a stain increases the contrast of a cell with its background. Staining a cell with a dye such as Giemsa stain or crystal violet allows a microscopist to describe its size, shape, internal and external components and its associations with other cells. The response of bacteria to different staining procedures is used in the taxonomic classification of microbes as well. Two methods, the Gram stain and the acid-fast stain, are the standard approaches used to classify bacteria and to diagnosis of disease. The Gram stain identifies the bacterial groups Bacillota and Actinomycetota , both of which contain many significant human pathogens. The acid-fast staining procedure identifies the Actinomycetota genera Mycobacterium and Nocardia . Biochemical tests used in the identification of infectious agents include the detection of metabolic or enzymatic products characteristic of a particular infectious agent. Since bacteria ferment carbohydrates in patterns characteristic of their genus and species , the detection of fermentation products is commonly used in bacterial identification. Acids , alcohols and gases are usually detected in these tests when bacteria are grown in selective liquid or solid media. The isolation of enzymes from infected tissue can also provide the basis of a biochemical diagnosis of an infectious disease. For example, humans can make neither RNA replicases nor reverse transcriptase , and the presence of these enzymes are characteristic., of specific types of viral infections. The ability of the viral protein hemagglutinin to bind red blood cells together into a detectable matrix may also be characterized as a biochemical test for viral infection, although strictly speaking hemagglutinin is not an enzyme and has no metabolic function. Serological methods are highly sensitive, specific and often extremely rapid tests used to identify microorganisms. These tests are based upon the ability of an antibody to bind specifically to an antigen. The antigen, usually a protein or carbohydrate made by an infectious agent, is bound by the antibody. This binding then sets off a chain of events that can be visibly obvious in various ways, dependent upon the test. For example, " Strep throat " is often diagnosed within minutes, and is based on the appearance of antigens made by the causative agent, S. pyogenes , that is retrieved from a patient's throat with a cotton swab. Serological tests, if available, are usually the preferred route of identification, however the tests are costly to develop and the reagents used in the test often require refrigeration . Some serological methods are extremely costly, although when commonly used, such as with the "strep test", they can be inexpensive. Complex serological techniques have been developed into what are known as immunoassays . Immunoassays can use the basic antibody – antigen binding as the basis to produce an electro-magnetic or particle radiation signal, which can be detected by some form of instrumentation. Signal of unknowns can be compared to that of standards allowing quantitation of the target antigen. To aid in the diagnosis of infectious diseases, immunoassays can detect or measure antigens from either infectious agents or proteins generated by an infected organism in response to a foreign agent. For example, immunoassay A may detect the presence of a surface protein from a virus particle. Immunoassay B on the other hand may detect or measure antibodies produced by an organism's immune system that are made to neutralize and allow the destruction of the virus. Instrumentation can be used to read extremely small signals created by secondary reactions linked to the antibody – antigen binding. Instrumentation can control sampling, reagent use, reaction times, signal detection, calculation of results, and data management to yield a cost-effective automated process for diagnosis of infectious disease. Technologies based upon the polymerase chain reaction (PCR) method will become nearly ubiquitous gold standards of diagnostics of the near future, for several reasons. First, the catalog of infectious agents has grown to the point that virtually all of the significant infectious agents of the human population have been identified. Second, an infectious agent must grow within the human body to cause disease; essentially it must amplify its own nucleic acids in order to cause a disease. This amplification of nucleic acid in infected tissue offers an opportunity to detect the infectious agent by using PCR. Third, the essential tools for directing PCR, primers , are derived from the genomes of infectious agents, and with time those genomes will be known, if they are not already. Thus, the technological ability to detect any infectious agent rapidly and specifically are currently available. The only remaining blockades to the use of PCR as a standard tool of diagnosis are in its cost and application, neither of which is insurmountable. The diagnosis of a few diseases will not benefit from the development of PCR methods, such as some of the clostridial diseases ( tetanus and botulism ). These diseases are fundamentally biological poisonings by relatively small numbers of infectious bacteria that produce extremely potent neurotoxins . A significant proliferation of the infectious agent does not occur, this limits the ability of PCR to detect the presence of any bacteria. Given the wide range of bacterial, viral, fungal, protozoal, and helminthic pathogens that cause debilitating and life-threatening illnesses, the ability to quickly identify the cause of infection is important yet often challenging. For example, more than half of cases of encephalitis , a severe illness affecting the brain, remain undiagnosed, despite extensive testing using the standard of care ( microbiological culture ) and state-of-the-art clinical laboratory methods. Metagenomic sequencing-based diagnostic tests are currently being developed for clinical use and show promise as a sensitive, specific, and rapid way to diagnose infection using a single all-encompassing test. This test is similar to current PCR tests; however, an untargeted whole genome amplification is used rather than primers for a specific infectious agent. This amplification step is followed by next-generation sequencing or third-generation sequencing , alignment comparisons , and taxonomic classification using large databases of thousands of pathogen and commensal reference genomes . Simultaneously, antimicrobial resistance genes within pathogen and plasmid genomes are sequenced and aligned to the taxonomically classified pathogen genomes to generate an antimicrobial resistance profile – analogous to antibiotic sensitivity testing – to facilitate antimicrobial stewardship and allow for the optimization of treatment using the most effective drugs for a patient's infection. Metagenomic sequencing could prove especially useful for diagnosis when the patient is immunocompromised . An ever-wider array of infectious agents can cause serious harm to individuals with immunosuppression, so clinical screening must often be broader. Additionally, the expression of symptoms is often atypical, making a clinical diagnosis based on presentation more difficult. Thirdly, diagnostic methods that rely on the detection of antibodies are more likely to fail. A rapid, sensitive, specific, and untargeted test for all known human pathogens that detects the presence of the organism's DNA rather than antibodies is therefore highly desirable. There is usually an indication for a specific identification of an infectious agent only when such identification can aid in the treatment or prevention of the disease, or to advance knowledge of the course of an illness prior to the development of effective therapeutic or preventative measures. For example, in the early 1980s, prior to the appearance of AZT for the treatment of AIDS , the course of the disease was closely followed by monitoring the composition of patient blood samples, even though the outcome would not offer the patient any further treatment options. In part, these studies on the appearance of HIV in specific communities permitted the advancement of hypotheses as to the route of transmission of the virus. By understanding how the disease was transmitted, resources could be targeted to the communities at greatest risk in campaigns aimed at reducing the number of new infections. The specific serological diagnostic identification, and later genotypic or molecular identification, of HIV also enabled the development of hypotheses as to the temporal and geographical origins of the virus, as well as a myriad of other hypothesis. The development of molecular diagnostic tools have enabled physicians and researchers to monitor the efficacy of treatment with anti-retroviral drugs . Molecular diagnostics are now commonly used to identify HIV in healthy people long before the onset of illness and have been used to demonstrate the existence of people who are genetically resistant to HIV infection. Thus, while there still is no cure for AIDS, there is great therapeutic and predictive benefit to identifying the virus and monitoring the virus levels within the blood of infected individuals, both for the patient and for the community at large. Symptomatic infections are apparent and clinical , whereas an infection that is active but does not produce noticeable symptoms may be called inapparent, silent, subclinical , or occult . An infection that is inactive or dormant is called a latent infection . An example of a latent bacterial infection is latent tuberculosis . Some viral infections can also be latent, examples of latent viral infections are any of those from the Herpesviridae family. The word infection can denote any presence of a particular pathogen at all (no matter how little) but also is often used in a sense implying a clinically apparent infection (in other words, a case of infectious disease). This fact occasionally creates some ambiguity or prompts some usage discussion; to get around this it is common for health professionals to speak of colonization (rather than infection ) when they mean that some of the pathogens are present but that no clinically apparent infection (no disease) is present. Different terms are used to describe how and where infections present over time. In an acute infection, symptoms develop rapidly; its course can either be rapid or protracted. In chronic infection, symptoms usually develop gradually over weeks or months and are slow to resolve. In subacute infections, symptoms take longer to develop than in acute infections but arise more quickly than those of chronic infections. A focal infection is an initial site of infection from which organisms travel via the bloodstream to another area of the body. Among the many varieties of microorganisms , relatively few cause disease in otherwise healthy individuals. Infectious disease results from the interplay between those few pathogens and the defenses of the hosts they infect. The appearance and severity of disease resulting from any pathogen depend upon the ability of that pathogen to damage the host as well as the ability of the host to resist the pathogen. However, a host's immune system can also cause damage to the host itself in an attempt to control the infection. Clinicians, therefore, classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens . Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence (the severity of the disease they cause) is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common primary pathogens of humans only infect humans, however, many serious diseases are caused by organisms acquired from the environment or that infect non-human hosts. Opportunistic pathogens can cause an infectious disease in a host with depressed resistance ( immunodeficiency ) or if they have unusual access to the inside of the body (for example, via trauma ). Opportunistic infection may be caused by microbes ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract , and they may also result from (otherwise innocuous) microbes acquired from other hosts (as in Clostridium difficile colitis ) or from the environment as a result of traumatic introduction (as in surgical wound infections or compound fractures ). An opportunistic disease requires impairment of host defenses, which may occur as a result of genetic defects (such as chronic granulomatous disease ), exposure to antimicrobial drugs or immunosuppressive chemicals (as might occur following poisoning or cancer chemotherapy ), exposure to ionizing radiation , or as a result of an infectious disease with immunosuppressive activity (such as with measles , malaria or HIV disease ). Primary pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host. While a primary infection can practically be viewed as the root cause of an individual's current health problem, a secondary infection is a sequela or complication of that root cause. For example, an infection due to a burn or penetrating trauma (the root cause) is a secondary infection. Primary pathogens often cause primary infection and often cause secondary infection. Usually, opportunistic infections are viewed as secondary infections (because immunodeficiency or injury was the predisposing factor). Other types of infection consist of mixed, iatrogenic , nosocomial , and community-acquired infection. A mixed infection is an infection that is caused by two or more pathogens. An example of this is appendicitis , which is caused by Bacteroides fragilis and Escherichia coli . The second is an iatrogenic infection. This type of infection is one that is transmitted from a health care worker to a patient. A nosocomial infection is also one that occurs in a health care setting. Nosocomial infections are those that are acquired during a hospital stay. Lastly, a community-acquired infection is one in which the infection is acquired from a whole community. One manner of proving that a given disease is infectious, is to satisfy Koch's postulates (first proposed by Robert Koch ), which require that first, the infectious agent be identifiable only in patients who have the disease, and not in healthy controls, and second, that patients who contract the infectious agent also develop the disease. These postulates were first used in the discovery that Mycobacteria species cause tuberculosis . However, Koch's postulates cannot usually be tested in modern practice for ethical reasons. Proving them would require experimental infection of a healthy individual with a pathogen produced as a pure culture. Conversely, even clearly infectious diseases do not always meet the infectious criteria; for example, Treponema pallidum , the causative spirochete of syphilis , cannot be cultured in vitro – however the organism can be cultured in rabbit testes . It is less clear that a pure culture comes from an animal source serving as host than it is when derived from microbes derived from plate culture. Epidemiology , or the study and analysis of who, why and where disease occurs, and what determines whether various populations have a disease, is another important tool used to understand infectious disease. Epidemiologists may determine differences among groups within a population, such as whether certain age groups have a greater or lesser rate of infection; whether groups living in different neighborhoods are more likely to be infected; and by other factors, such as gender and race. Researchers also may assess whether a disease outbreak is sporadic, or just an occasional occurrence; endemic , with a steady level of regular cases occurring in a region; epidemic , with a fast arising, and unusually high number of cases in a region; or pandemic , which is a global epidemic. If the cause of the infectious disease is unknown, epidemiology can be used to assist with tracking down the sources of infection. Infectious diseases are sometimes called contagious diseases when they are easily transmitted by contact with an ill person or their secretions (e.g., influenza ). Thus, a contagious disease is a subset of infectious disease that is especially infective or easily transmitted. Other types of infectious, transmissible, or communicable diseases with more specialized routes of infection, such as vector transmission or sexual transmission, are usually not regarded as "contagious", and often do not require medical isolation (sometimes loosely called quarantine ) of those affected. However, this specialized connotation of the word "contagious" and "contagious disease" (easy transmissibility) is not always respected in popular use. Infectious diseases are commonly transmitted from person to person through direct contact. The types of contact are through person to person and droplet spread. Indirect contact such as airborne transmission, contaminated objects, food and drinking water, animal person contact, animal reservoirs, insect bites, and environmental reservoirs are another way infectious diseases are transmitted. Infections can be classified by the anatomic location or organ system infected, including: [ citation needed ] In addition, locations of inflammation where infection is the most common cause include pneumonia , meningitis and salpingitis . [ citation needed ]The diagnosis is aided by the presenting symptoms in any individual with an infectious disease, yet it usually needs additional diagnostic techniques to confirm the suspicion. Some signs are specifically characteristic and indicative of a disease and are called pathognomonic signs; but these are rare. Not all infections are symptomatic. In children the presence of cyanosis , rapid breathing, poor peripheral perfusion, or a petechial rash increases the risk of a serious infection by greater than 5 fold. Other important indicators include parental concern, clinical instinct, and temperature greater than 40 °C. Many diagnostic approaches depend on microbiological culture to isolate a pathogen from the appropriate clinical specimen. In a microbial culture, a growth medium is provided for a specific agent. A sample taken from potentially diseased tissue or fluid is then tested for the presence of an infectious agent able to grow within that medium. Many pathogenic bacteria are easily grown on nutrient agar , a form of solid medium that supplies carbohydrates and proteins necessary for growth, along with copious amounts of water. A single bacterium will grow into a visible mound on the surface of the plate called a colony , which may be separated from other colonies or melded together into a "lawn". The size, color, shape and form of a colony is characteristic of the bacterial species, its specific genetic makeup (its strain ), and the environment that supports its growth. Other ingredients are often added to the plate to aid in identification. Plates may contain substances that permit the growth of some bacteria and not others, or that change color in response to certain bacteria and not others. Bacteriological plates such as these are commonly used in the clinical identification of infectious bacterium. Microbial culture may also be used in the identification of viruses : the medium, in this case, being cells grown in culture that the virus can infect, and then alter or kill. In the case of viral identification, a region of dead cells results from viral growth, and is called a "plaque". Eukaryotic parasites may also be grown in culture as a means of identifying a particular agent. In the absence of suitable plate culture techniques, some microbes require culture within live animals. Bacteria such as Mycobacterium leprae and Treponema pallidum can be grown in animals, although serological and microscopic techniques make the use of live animals unnecessary. Viruses are also usually identified using alternatives to growth in culture or animals. Some viruses may be grown in embryonated eggs. Another useful identification method is Xenodiagnosis, or the use of a vector to support the growth of an infectious agent. Chagas disease is the most significant example, because it is difficult to directly demonstrate the presence of the causative agent, Trypanosoma cruzi in a patient, which therefore makes it difficult to definitively make a diagnosis. In this case, xenodiagnosis involves the use of the vector of the Chagas agent T. cruzi , an uninfected triatomine bug, which takes a blood meal from a person suspected of having been infected. The bug is later inspected for growth of T. cruzi within its gut. Another principal tool in the diagnosis of infectious disease is microscopy . Virtually all of the culture techniques discussed above rely, at some point, on microscopic examination for definitive identification of the infectious agent. Microscopy may be carried out with simple instruments, such as the compound light microscope , or with instruments as complex as an electron microscope . Samples obtained from patients may be viewed directly under the light microscope, and can often rapidly lead to identification. Microscopy is often also used in conjunction with biochemical staining techniques, and can be made exquisitely specific when used in combination with antibody based techniques. For example, the use of antibodies made artificially fluorescent (fluorescently labeled antibodies) can be directed to bind to and identify a specific antigens present on a pathogen. A fluorescence microscope is then used to detect fluorescently labeled antibodies bound to internalized antigens within clinical samples or cultured cells. This technique is especially useful in the diagnosis of viral diseases, where the light microscope is incapable of identifying a virus directly. Other microscopic procedures may also aid in identifying infectious agents. Almost all cells readily stain with a number of basic dyes due to the electrostatic attraction between negatively charged cellular molecules and the positive charge on the dye. A cell is normally transparent under a microscope, and using a stain increases the contrast of a cell with its background. Staining a cell with a dye such as Giemsa stain or crystal violet allows a microscopist to describe its size, shape, internal and external components and its associations with other cells. The response of bacteria to different staining procedures is used in the taxonomic classification of microbes as well. Two methods, the Gram stain and the acid-fast stain, are the standard approaches used to classify bacteria and to diagnosis of disease. The Gram stain identifies the bacterial groups Bacillota and Actinomycetota , both of which contain many significant human pathogens. The acid-fast staining procedure identifies the Actinomycetota genera Mycobacterium and Nocardia . Biochemical tests used in the identification of infectious agents include the detection of metabolic or enzymatic products characteristic of a particular infectious agent. Since bacteria ferment carbohydrates in patterns characteristic of their genus and species , the detection of fermentation products is commonly used in bacterial identification. Acids , alcohols and gases are usually detected in these tests when bacteria are grown in selective liquid or solid media. The isolation of enzymes from infected tissue can also provide the basis of a biochemical diagnosis of an infectious disease. For example, humans can make neither RNA replicases nor reverse transcriptase , and the presence of these enzymes are characteristic., of specific types of viral infections. The ability of the viral protein hemagglutinin to bind red blood cells together into a detectable matrix may also be characterized as a biochemical test for viral infection, although strictly speaking hemagglutinin is not an enzyme and has no metabolic function. Serological methods are highly sensitive, specific and often extremely rapid tests used to identify microorganisms. These tests are based upon the ability of an antibody to bind specifically to an antigen. The antigen, usually a protein or carbohydrate made by an infectious agent, is bound by the antibody. This binding then sets off a chain of events that can be visibly obvious in various ways, dependent upon the test. For example, " Strep throat " is often diagnosed within minutes, and is based on the appearance of antigens made by the causative agent, S. pyogenes , that is retrieved from a patient's throat with a cotton swab. Serological tests, if available, are usually the preferred route of identification, however the tests are costly to develop and the reagents used in the test often require refrigeration . Some serological methods are extremely costly, although when commonly used, such as with the "strep test", they can be inexpensive. Complex serological techniques have been developed into what are known as immunoassays . Immunoassays can use the basic antibody – antigen binding as the basis to produce an electro-magnetic or particle radiation signal, which can be detected by some form of instrumentation. Signal of unknowns can be compared to that of standards allowing quantitation of the target antigen. To aid in the diagnosis of infectious diseases, immunoassays can detect or measure antigens from either infectious agents or proteins generated by an infected organism in response to a foreign agent. For example, immunoassay A may detect the presence of a surface protein from a virus particle. Immunoassay B on the other hand may detect or measure antibodies produced by an organism's immune system that are made to neutralize and allow the destruction of the virus. Instrumentation can be used to read extremely small signals created by secondary reactions linked to the antibody – antigen binding. Instrumentation can control sampling, reagent use, reaction times, signal detection, calculation of results, and data management to yield a cost-effective automated process for diagnosis of infectious disease.Technologies based upon the polymerase chain reaction (PCR) method will become nearly ubiquitous gold standards of diagnostics of the near future, for several reasons. First, the catalog of infectious agents has grown to the point that virtually all of the significant infectious agents of the human population have been identified. Second, an infectious agent must grow within the human body to cause disease; essentially it must amplify its own nucleic acids in order to cause a disease. This amplification of nucleic acid in infected tissue offers an opportunity to detect the infectious agent by using PCR. Third, the essential tools for directing PCR, primers , are derived from the genomes of infectious agents, and with time those genomes will be known, if they are not already. Thus, the technological ability to detect any infectious agent rapidly and specifically are currently available. The only remaining blockades to the use of PCR as a standard tool of diagnosis are in its cost and application, neither of which is insurmountable. The diagnosis of a few diseases will not benefit from the development of PCR methods, such as some of the clostridial diseases ( tetanus and botulism ). These diseases are fundamentally biological poisonings by relatively small numbers of infectious bacteria that produce extremely potent neurotoxins . A significant proliferation of the infectious agent does not occur, this limits the ability of PCR to detect the presence of any bacteria. Given the wide range of bacterial, viral, fungal, protozoal, and helminthic pathogens that cause debilitating and life-threatening illnesses, the ability to quickly identify the cause of infection is important yet often challenging. For example, more than half of cases of encephalitis , a severe illness affecting the brain, remain undiagnosed, despite extensive testing using the standard of care ( microbiological culture ) and state-of-the-art clinical laboratory methods. Metagenomic sequencing-based diagnostic tests are currently being developed for clinical use and show promise as a sensitive, specific, and rapid way to diagnose infection using a single all-encompassing test. This test is similar to current PCR tests; however, an untargeted whole genome amplification is used rather than primers for a specific infectious agent. This amplification step is followed by next-generation sequencing or third-generation sequencing , alignment comparisons , and taxonomic classification using large databases of thousands of pathogen and commensal reference genomes . Simultaneously, antimicrobial resistance genes within pathogen and plasmid genomes are sequenced and aligned to the taxonomically classified pathogen genomes to generate an antimicrobial resistance profile – analogous to antibiotic sensitivity testing – to facilitate antimicrobial stewardship and allow for the optimization of treatment using the most effective drugs for a patient's infection. Metagenomic sequencing could prove especially useful for diagnosis when the patient is immunocompromised . An ever-wider array of infectious agents can cause serious harm to individuals with immunosuppression, so clinical screening must often be broader. Additionally, the expression of symptoms is often atypical, making a clinical diagnosis based on presentation more difficult. Thirdly, diagnostic methods that rely on the detection of antibodies are more likely to fail. A rapid, sensitive, specific, and untargeted test for all known human pathogens that detects the presence of the organism's DNA rather than antibodies is therefore highly desirable.There is usually an indication for a specific identification of an infectious agent only when such identification can aid in the treatment or prevention of the disease, or to advance knowledge of the course of an illness prior to the development of effective therapeutic or preventative measures. For example, in the early 1980s, prior to the appearance of AZT for the treatment of AIDS , the course of the disease was closely followed by monitoring the composition of patient blood samples, even though the outcome would not offer the patient any further treatment options. In part, these studies on the appearance of HIV in specific communities permitted the advancement of hypotheses as to the route of transmission of the virus. By understanding how the disease was transmitted, resources could be targeted to the communities at greatest risk in campaigns aimed at reducing the number of new infections. The specific serological diagnostic identification, and later genotypic or molecular identification, of HIV also enabled the development of hypotheses as to the temporal and geographical origins of the virus, as well as a myriad of other hypothesis. The development of molecular diagnostic tools have enabled physicians and researchers to monitor the efficacy of treatment with anti-retroviral drugs . Molecular diagnostics are now commonly used to identify HIV in healthy people long before the onset of illness and have been used to demonstrate the existence of people who are genetically resistant to HIV infection. Thus, while there still is no cure for AIDS, there is great therapeutic and predictive benefit to identifying the virus and monitoring the virus levels within the blood of infected individuals, both for the patient and for the community at large.Symptomatic infections are apparent and clinical , whereas an infection that is active but does not produce noticeable symptoms may be called inapparent, silent, subclinical , or occult . An infection that is inactive or dormant is called a latent infection . An example of a latent bacterial infection is latent tuberculosis . Some viral infections can also be latent, examples of latent viral infections are any of those from the Herpesviridae family. The word infection can denote any presence of a particular pathogen at all (no matter how little) but also is often used in a sense implying a clinically apparent infection (in other words, a case of infectious disease). This fact occasionally creates some ambiguity or prompts some usage discussion; to get around this it is common for health professionals to speak of colonization (rather than infection ) when they mean that some of the pathogens are present but that no clinically apparent infection (no disease) is present. Different terms are used to describe how and where infections present over time. In an acute infection, symptoms develop rapidly; its course can either be rapid or protracted. In chronic infection, symptoms usually develop gradually over weeks or months and are slow to resolve. In subacute infections, symptoms take longer to develop than in acute infections but arise more quickly than those of chronic infections. A focal infection is an initial site of infection from which organisms travel via the bloodstream to another area of the body. Among the many varieties of microorganisms , relatively few cause disease in otherwise healthy individuals. Infectious disease results from the interplay between those few pathogens and the defenses of the hosts they infect. The appearance and severity of disease resulting from any pathogen depend upon the ability of that pathogen to damage the host as well as the ability of the host to resist the pathogen. However, a host's immune system can also cause damage to the host itself in an attempt to control the infection. Clinicians, therefore, classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens . Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence (the severity of the disease they cause) is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common primary pathogens of humans only infect humans, however, many serious diseases are caused by organisms acquired from the environment or that infect non-human hosts. Opportunistic pathogens can cause an infectious disease in a host with depressed resistance ( immunodeficiency ) or if they have unusual access to the inside of the body (for example, via trauma ). Opportunistic infection may be caused by microbes ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract , and they may also result from (otherwise innocuous) microbes acquired from other hosts (as in Clostridium difficile colitis ) or from the environment as a result of traumatic introduction (as in surgical wound infections or compound fractures ). An opportunistic disease requires impairment of host defenses, which may occur as a result of genetic defects (such as chronic granulomatous disease ), exposure to antimicrobial drugs or immunosuppressive chemicals (as might occur following poisoning or cancer chemotherapy ), exposure to ionizing radiation , or as a result of an infectious disease with immunosuppressive activity (such as with measles , malaria or HIV disease ). Primary pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host. While a primary infection can practically be viewed as the root cause of an individual's current health problem, a secondary infection is a sequela or complication of that root cause. For example, an infection due to a burn or penetrating trauma (the root cause) is a secondary infection. Primary pathogens often cause primary infection and often cause secondary infection. Usually, opportunistic infections are viewed as secondary infections (because immunodeficiency or injury was the predisposing factor). Other types of infection consist of mixed, iatrogenic , nosocomial , and community-acquired infection. A mixed infection is an infection that is caused by two or more pathogens. An example of this is appendicitis , which is caused by Bacteroides fragilis and Escherichia coli . The second is an iatrogenic infection. This type of infection is one that is transmitted from a health care worker to a patient. A nosocomial infection is also one that occurs in a health care setting. Nosocomial infections are those that are acquired during a hospital stay. Lastly, a community-acquired infection is one in which the infection is acquired from a whole community. One manner of proving that a given disease is infectious, is to satisfy Koch's postulates (first proposed by Robert Koch ), which require that first, the infectious agent be identifiable only in patients who have the disease, and not in healthy controls, and second, that patients who contract the infectious agent also develop the disease. These postulates were first used in the discovery that Mycobacteria species cause tuberculosis . However, Koch's postulates cannot usually be tested in modern practice for ethical reasons. Proving them would require experimental infection of a healthy individual with a pathogen produced as a pure culture. Conversely, even clearly infectious diseases do not always meet the infectious criteria; for example, Treponema pallidum , the causative spirochete of syphilis , cannot be cultured in vitro – however the organism can be cultured in rabbit testes . It is less clear that a pure culture comes from an animal source serving as host than it is when derived from microbes derived from plate culture. Epidemiology , or the study and analysis of who, why and where disease occurs, and what determines whether various populations have a disease, is another important tool used to understand infectious disease. Epidemiologists may determine differences among groups within a population, such as whether certain age groups have a greater or lesser rate of infection; whether groups living in different neighborhoods are more likely to be infected; and by other factors, such as gender and race. Researchers also may assess whether a disease outbreak is sporadic, or just an occasional occurrence; endemic , with a steady level of regular cases occurring in a region; epidemic , with a fast arising, and unusually high number of cases in a region; or pandemic , which is a global epidemic. If the cause of the infectious disease is unknown, epidemiology can be used to assist with tracking down the sources of infection. Infectious diseases are sometimes called contagious diseases when they are easily transmitted by contact with an ill person or their secretions (e.g., influenza ). Thus, a contagious disease is a subset of infectious disease that is especially infective or easily transmitted. Other types of infectious, transmissible, or communicable diseases with more specialized routes of infection, such as vector transmission or sexual transmission, are usually not regarded as "contagious", and often do not require medical isolation (sometimes loosely called quarantine ) of those affected. However, this specialized connotation of the word "contagious" and "contagious disease" (easy transmissibility) is not always respected in popular use. Infectious diseases are commonly transmitted from person to person through direct contact. The types of contact are through person to person and droplet spread. Indirect contact such as airborne transmission, contaminated objects, food and drinking water, animal person contact, animal reservoirs, insect bites, and environmental reservoirs are another way infectious diseases are transmitted. Infections can be classified by the anatomic location or organ system infected, including: [ citation needed ] In addition, locations of inflammation where infection is the most common cause include pneumonia , meningitis and salpingitis . [ citation needed ]Symptomatic infections are apparent and clinical , whereas an infection that is active but does not produce noticeable symptoms may be called inapparent, silent, subclinical , or occult . An infection that is inactive or dormant is called a latent infection . An example of a latent bacterial infection is latent tuberculosis . Some viral infections can also be latent, examples of latent viral infections are any of those from the Herpesviridae family. The word infection can denote any presence of a particular pathogen at all (no matter how little) but also is often used in a sense implying a clinically apparent infection (in other words, a case of infectious disease). This fact occasionally creates some ambiguity or prompts some usage discussion; to get around this it is common for health professionals to speak of colonization (rather than infection ) when they mean that some of the pathogens are present but that no clinically apparent infection (no disease) is present. Different terms are used to describe how and where infections present over time. In an acute infection, symptoms develop rapidly; its course can either be rapid or protracted. In chronic infection, symptoms usually develop gradually over weeks or months and are slow to resolve. In subacute infections, symptoms take longer to develop than in acute infections but arise more quickly than those of chronic infections. A focal infection is an initial site of infection from which organisms travel via the bloodstream to another area of the body. Among the many varieties of microorganisms , relatively few cause disease in otherwise healthy individuals. Infectious disease results from the interplay between those few pathogens and the defenses of the hosts they infect. The appearance and severity of disease resulting from any pathogen depend upon the ability of that pathogen to damage the host as well as the ability of the host to resist the pathogen. However, a host's immune system can also cause damage to the host itself in an attempt to control the infection. Clinicians, therefore, classify infectious microorganisms or microbes according to the status of host defenses – either as primary pathogens or as opportunistic pathogens . Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence (the severity of the disease they cause) is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common primary pathogens of humans only infect humans, however, many serious diseases are caused by organisms acquired from the environment or that infect non-human hosts. Opportunistic pathogens can cause an infectious disease in a host with depressed resistance ( immunodeficiency ) or if they have unusual access to the inside of the body (for example, via trauma ). Opportunistic infection may be caused by microbes ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract , and they may also result from (otherwise innocuous) microbes acquired from other hosts (as in Clostridium difficile colitis ) or from the environment as a result of traumatic introduction (as in surgical wound infections or compound fractures ). An opportunistic disease requires impairment of host defenses, which may occur as a result of genetic defects (such as chronic granulomatous disease ), exposure to antimicrobial drugs or immunosuppressive chemicals (as might occur following poisoning or cancer chemotherapy ), exposure to ionizing radiation , or as a result of an infectious disease with immunosuppressive activity (such as with measles , malaria or HIV disease ). Primary pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host. While a primary infection can practically be viewed as the root cause of an individual's current health problem, a secondary infection is a sequela or complication of that root cause. For example, an infection due to a burn or penetrating trauma (the root cause) is a secondary infection. Primary pathogens often cause primary infection and often cause secondary infection. Usually, opportunistic infections are viewed as secondary infections (because immunodeficiency or injury was the predisposing factor). Other types of infection consist of mixed, iatrogenic , nosocomial , and community-acquired infection. A mixed infection is an infection that is caused by two or more pathogens. An example of this is appendicitis , which is caused by Bacteroides fragilis and Escherichia coli . The second is an iatrogenic infection. This type of infection is one that is transmitted from a health care worker to a patient. A nosocomial infection is also one that occurs in a health care setting. Nosocomial infections are those that are acquired during a hospital stay. Lastly, a community-acquired infection is one in which the infection is acquired from a whole community. Primary pathogens cause disease as a result of their presence or activity within the normal, healthy host, and their intrinsic virulence (the severity of the disease they cause) is, in part, a necessary consequence of their need to reproduce and spread. Many of the most common primary pathogens of humans only infect humans, however, many serious diseases are caused by organisms acquired from the environment or that infect non-human hosts. Opportunistic pathogens can cause an infectious disease in a host with depressed resistance ( immunodeficiency ) or if they have unusual access to the inside of the body (for example, via trauma ). Opportunistic infection may be caused by microbes ordinarily in contact with the host, such as pathogenic bacteria or fungi in the gastrointestinal or the upper respiratory tract , and they may also result from (otherwise innocuous) microbes acquired from other hosts (as in Clostridium difficile colitis ) or from the environment as a result of traumatic introduction (as in surgical wound infections or compound fractures ). An opportunistic disease requires impairment of host defenses, which may occur as a result of genetic defects (such as chronic granulomatous disease ), exposure to antimicrobial drugs or immunosuppressive chemicals (as might occur following poisoning or cancer chemotherapy ), exposure to ionizing radiation , or as a result of an infectious disease with immunosuppressive activity (such as with measles , malaria or HIV disease ). Primary pathogens may also cause more severe disease in a host with depressed resistance than would normally occur in an immunosufficient host. While a primary infection can practically be viewed as the root cause of an individual's current health problem, a secondary infection is a sequela or complication of that root cause. For example, an infection due to a burn or penetrating trauma (the root cause) is a secondary infection. Primary pathogens often cause primary infection and often cause secondary infection. Usually, opportunistic infections are viewed as secondary infections (because immunodeficiency or injury was the predisposing factor). Other types of infection consist of mixed, iatrogenic , nosocomial , and community-acquired infection. A mixed infection is an infection that is caused by two or more pathogens. An example of this is appendicitis , which is caused by Bacteroides fragilis and Escherichia coli . The second is an iatrogenic infection. This type of infection is one that is transmitted from a health care worker to a patient. A nosocomial infection is also one that occurs in a health care setting. Nosocomial infections are those that are acquired during a hospital stay. Lastly, a community-acquired infection is one in which the infection is acquired from a whole community. One manner of proving that a given disease is infectious, is to satisfy Koch's postulates (first proposed by Robert Koch ), which require that first, the infectious agent be identifiable only in patients who have the disease, and not in healthy controls, and second, that patients who contract the infectious agent also develop the disease. These postulates were first used in the discovery that Mycobacteria species cause tuberculosis . However, Koch's postulates cannot usually be tested in modern practice for ethical reasons. Proving them would require experimental infection of a healthy individual with a pathogen produced as a pure culture. Conversely, even clearly infectious diseases do not always meet the infectious criteria; for example, Treponema pallidum , the causative spirochete of syphilis , cannot be cultured in vitro – however the organism can be cultured in rabbit testes . It is less clear that a pure culture comes from an animal source serving as host than it is when derived from microbes derived from plate culture. Epidemiology , or the study and analysis of who, why and where disease occurs, and what determines whether various populations have a disease, is another important tool used to understand infectious disease. Epidemiologists may determine differences among groups within a population, such as whether certain age groups have a greater or lesser rate of infection; whether groups living in different neighborhoods are more likely to be infected; and by other factors, such as gender and race. Researchers also may assess whether a disease outbreak is sporadic, or just an occasional occurrence; endemic , with a steady level of regular cases occurring in a region; epidemic , with a fast arising, and unusually high number of cases in a region; or pandemic , which is a global epidemic. If the cause of the infectious disease is unknown, epidemiology can be used to assist with tracking down the sources of infection. Infectious diseases are sometimes called contagious diseases when they are easily transmitted by contact with an ill person or their secretions (e.g., influenza ). Thus, a contagious disease is a subset of infectious disease that is especially infective or easily transmitted. Other types of infectious, transmissible, or communicable diseases with more specialized routes of infection, such as vector transmission or sexual transmission, are usually not regarded as "contagious", and often do not require medical isolation (sometimes loosely called quarantine ) of those affected. However, this specialized connotation of the word "contagious" and "contagious disease" (easy transmissibility) is not always respected in popular use. Infectious diseases are commonly transmitted from person to person through direct contact. The types of contact are through person to person and droplet spread. Indirect contact such as airborne transmission, contaminated objects, food and drinking water, animal person contact, animal reservoirs, insect bites, and environmental reservoirs are another way infectious diseases are transmitted. Infections can be classified by the anatomic location or organ system infected, including: [ citation needed ] In addition, locations of inflammation where infection is the most common cause include pneumonia , meningitis and salpingitis . [ citation needed ]Techniques like hand washing, wearing gowns, and wearing face masks can help prevent infections from being passed from one person to another. Aseptic technique was introduced in medicine and surgery in the late 19th century and greatly reduced the incidence of infections caused by surgery. Frequent hand washing remains the most important defense against the spread of unwanted organisms. There are other forms of prevention such as avoiding the use of illicit drugs, using a condom , wearing gloves, and having a healthy lifestyle with a balanced diet and regular exercise. Cooking foods well and avoiding foods that have been left outside for a long time is also important. [ citation needed ] Antimicrobial substances used to prevent transmission of infections include: [ citation needed ] One of the ways to prevent or slow down the transmission of infectious diseases is to recognize the different characteristics of various diseases. Some critical disease characteristics that should be evaluated include virulence , distance traveled by those affected, and level of contagiousness. The human strains of Ebola virus, for example, incapacitate those infected extremely quickly and kill them soon after. As a result, those affected by this disease do not have the opportunity to travel very far from the initial infection zone. Also, this virus must spread through skin lesions or permeable membranes such as the eye. Thus, the initial stage of Ebola is not very contagious since its victims experience only internal hemorrhaging. As a result of the above features, the spread of Ebola is very rapid and usually stays within a relatively confined geographical area. In contrast, the human immunodeficiency virus ( HIV ) kills its victims very slowly by attacking their immune system. As a result, many of its victims transmit the virus to other individuals before even realizing that they are carrying the disease. Also, the relatively low virulence allows its victims to travel long distances, increasing the likelihood of an epidemic . [ citation needed ] Another effective way to decrease the transmission rate of infectious diseases is to recognize the effects of small-world networks . In epidemics, there are often extensive interactions within hubs or groups of infected individuals and other interactions within discrete hubs of susceptible individuals. Despite the low interaction between discrete hubs, the disease can jump and spread in a susceptible hub via a single or few interactions with an infected hub. Thus, infection rates in small-world networks can be reduced somewhat if interactions between individuals within infected hubs are eliminated (Figure 1). However, infection rates can be drastically reduced if the main focus is on the prevention of transmission jumps between hubs. The use of needle exchange programs in areas with a high density of drug users with HIV is an example of the successful implementation of this treatment method. Another example is the use of ring culling or vaccination of potentially susceptible livestock in adjacent farms to prevent the spread of the foot-and-mouth virus in 2001. A general method to prevent transmission of vector -borne pathogens is pest control . In cases where infection is merely suspected, individuals may be quarantined until the incubation period has passed and the disease manifests itself or the person remains healthy. Groups may undergo quarantine, or in the case of communities, a cordon sanitaire may be imposed to prevent infection from spreading beyond the community, or in the case of protective sequestration , into a community. Public health authorities may implement other forms of social distancing , such as school closings, lockdowns or temporary restrictions (e.g. circuit breakers ) to control an epidemic. Infection with most pathogens does not result in death of the host and the offending organism is ultimately cleared after the symptoms of the disease have waned. This process requires immune mechanisms to kill or inactivate the inoculum of the pathogen. Specific acquired immunity against infectious diseases may be mediated by antibodies and/or T lymphocytes . Immunity mediated by these two factors may be manifested by: The immune system response to a microorganism often causes symptoms such as a high fever and inflammation , and has the potential to be more devastating than direct damage caused by a microbe. Resistance to infection ( immunity ) may be acquired following a disease, by asymptomatic carriage of the pathogen, by harboring an organism with a similar structure (crossreacting), or by vaccination . Knowledge of the protective antigens and specific acquired host immune factors is more complete for primary pathogens than for opportunistic pathogens . There is also the phenomenon of herd immunity which offers a measure of protection to those otherwise vulnerable people when a large enough proportion of the population has acquired immunity from certain infections. Immune resistance to an infectious disease requires a critical level of either antigen-specific antibodies and/or T cells when the host encounters the pathogen. Some individuals develop natural serum antibodies to the surface polysaccharides of some agents although they have had little or no contact with the agent, these natural antibodies confer specific protection to adults and are passively transmitted to newborns. The organism that is the target of an infecting action of a specific infectious agent is called the host. The host harbouring an agent that is in a mature or sexually active stage phase is called the definitive host. The intermediate host comes in contact during the larvae stage. A host can be anything living and can attain to asexual and sexual reproduction. The clearance of the pathogens, either treatment-induced or spontaneous, it can be influenced by the genetic variants carried by the individual patients. For instance, for genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin , it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in the treatment-induced clearance of the virus. This finding, originally reported in Nature , showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.Infection with most pathogens does not result in death of the host and the offending organism is ultimately cleared after the symptoms of the disease have waned. This process requires immune mechanisms to kill or inactivate the inoculum of the pathogen. Specific acquired immunity against infectious diseases may be mediated by antibodies and/or T lymphocytes . Immunity mediated by these two factors may be manifested by: The immune system response to a microorganism often causes symptoms such as a high fever and inflammation , and has the potential to be more devastating than direct damage caused by a microbe. Resistance to infection ( immunity ) may be acquired following a disease, by asymptomatic carriage of the pathogen, by harboring an organism with a similar structure (crossreacting), or by vaccination . Knowledge of the protective antigens and specific acquired host immune factors is more complete for primary pathogens than for opportunistic pathogens . There is also the phenomenon of herd immunity which offers a measure of protection to those otherwise vulnerable people when a large enough proportion of the population has acquired immunity from certain infections. Immune resistance to an infectious disease requires a critical level of either antigen-specific antibodies and/or T cells when the host encounters the pathogen. Some individuals develop natural serum antibodies to the surface polysaccharides of some agents although they have had little or no contact with the agent, these natural antibodies confer specific protection to adults and are passively transmitted to newborns. The organism that is the target of an infecting action of a specific infectious agent is called the host. The host harbouring an agent that is in a mature or sexually active stage phase is called the definitive host. The intermediate host comes in contact during the larvae stage. A host can be anything living and can attain to asexual and sexual reproduction. The clearance of the pathogens, either treatment-induced or spontaneous, it can be influenced by the genetic variants carried by the individual patients. For instance, for genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin , it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in the treatment-induced clearance of the virus. This finding, originally reported in Nature , showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.The organism that is the target of an infecting action of a specific infectious agent is called the host. The host harbouring an agent that is in a mature or sexually active stage phase is called the definitive host. The intermediate host comes in contact during the larvae stage. A host can be anything living and can attain to asexual and sexual reproduction. The clearance of the pathogens, either treatment-induced or spontaneous, it can be influenced by the genetic variants carried by the individual patients. For instance, for genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b (brand names Pegasys or PEG-Intron) combined with ribavirin , it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in the treatment-induced clearance of the virus. This finding, originally reported in Nature , showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more possibly to achieve sustained virological response after the treatment than others. Later report from Nature demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.When infection attacks the body, anti-infective drugs can suppress the infection. Several broad types of anti-infective drugs exist, depending on the type of organism targeted; they include antibacterial ( antibiotic ; including antitubercular ), antiviral , antifungal and antiparasitic (including antiprotozoal and antihelminthic ) agents. Depending on the severity and the type of infection, the antibiotic may be given by mouth or by injection, or may be applied topically . Severe infections of the brain are usually treated with intravenous antibiotics. Sometimes, multiple antibiotics are used in case there is resistance to one antibiotic. Antibiotics only work for bacteria and do not affect viruses. Antibiotics work by slowing down the multiplication of bacteria or killing the bacteria. The most common classes of antibiotics used in medicine include penicillin , cephalosporins , aminoglycosides , macrolides , quinolones and tetracyclines . Not all infections require treatment, and for many self-limiting infections the treatment may cause more side-effects than benefits. Antimicrobial stewardship is the concept that healthcare providers should treat an infection with an antimicrobial that specifically works well for the target pathogen for the shortest amount of time and to only treat when there is a known or highly suspected pathogen that will respond to the medication. Pandemics such as COVID-19 show that people dramatically differ in their susceptibility to infection. This may be because of general health, age, or their immune status, e.g. when they have been infected previously. However, it also has become clear that there are genetic factor which determine susceptibility to infection. For instance, up to 40% of SARS-CoV-2 infections may be asymptomatic, suggesting that many people are naturally protected from disease. Large genetic studies have defined risk factors for severe SARS-CoV-2 infections, and genome sequences from 659 patients with severe COVID-19 revealed genetic variants that appear to be associated with life-threatening disease. One gene identified in these studies is type I interferon (IFN). Autoantibodies against type I IFNs were found in up to 13.7% of patients with life-threatening COVID-19, indicating that a complex interaction between genetics and the immune system is important for natural resistance to Covid. Similarly, mutations in the ERAP2 gene, encoding endoplasmic reticulum aminopeptidase 2, seem to increase the susceptibility to the plague , the disease caused by an infection with the bacteria Yersinia pestis . People who inherited two copies of a complete variant of the gene were twice as likely to have survived the plague as those who inherited two copies of a truncated variant. Susceptibility also determined the epidemiology of infection, given that different populations have different genetic and environmental conditions that affect infections.no data ≤250 250–500 500–1000 1000–2000 2000–3000 3000–4000 4000–5000 5000–6250 6250–12,500 12,500–25,000 25,000–50,000 ≥50,000 In 2010, about 10 million people died of infectious diseases. The World Health Organization collects information on global deaths by International Classification of Disease (ICD) code categories . The following table lists the top infectious disease by number of deaths in 2002. 1993 data is included for comparison. The top three single agent/disease killers are HIV / AIDS , TB and malaria . While the number of deaths due to nearly every disease have decreased, deaths due to HIV/AIDS have increased fourfold. Childhood diseases include pertussis , poliomyelitis , diphtheria , measles and tetanus . Children also make up a large percentage of lower respiratory and diarrheal deaths. In 2012, approximately 3.1 million people have died due to lower respiratory infections, making it the number 4 leading cause of death in the world. With their potential for unpredictable and explosive impacts, infectious diseases have been major actors in human history . A pandemic (or global epidemic ) is a disease that affects people over an extensive geographical area. For example: In most cases, microorganisms live in harmony with their hosts via mutual or commensal interactions. Diseases can emerge when existing parasites become pathogenic or when new pathogenic parasites enter a new host. Several human activities have led to the emergence of zoonotic human pathogens, including viruses, bacteria, protozoa, and rickettsia, and spread of vector-borne diseases, see also globalization and disease and wildlife disease :With their potential for unpredictable and explosive impacts, infectious diseases have been major actors in human history . A pandemic (or global epidemic ) is a disease that affects people over an extensive geographical area. For example:In most cases, microorganisms live in harmony with their hosts via mutual or commensal interactions. Diseases can emerge when existing parasites become pathogenic or when new pathogenic parasites enter a new host. Several human activities have led to the emergence of zoonotic human pathogens, including viruses, bacteria, protozoa, and rickettsia, and spread of vector-borne diseases, see also globalization and disease and wildlife disease :In Antiquity , the Greek historian Thucydides ( c. 460 – c. 400 BCE ) was the first person to write, in his account of the plague of Athens , that diseases could spread from an infected person to others. In his On the Different Types of Fever ( c. 175 AD ), the Greco-Roman physician Galen speculated that plagues were spread by "certain seeds of plague", which were present in the air. In the Sushruta Samhita , the ancient Indian physician Sushruta theorized: "Leprosy, fever, consumption, diseases of the eye, and other infectious diseases spread from one person to another by sexual union, physical contact, eating together, sleeping together, sitting together, and the use of same clothes, garlands and pastes." This book has been dated to about the sixth century BC. A basic form of contagion theory was proposed by Persian physician Ibn Sina (known as Avicenna in Europe) in The Canon of Medicine (1025), which later became the most authoritative medical textbook in Europe up until the 16th century. In Book IV of the Canon , Ibn Sina discussed epidemics , outlining the classical miasma theory and attempting to blend it with his own early contagion theory. He mentioned that people can transmit disease to others by breath, noted contagion with tuberculosis , and discussed the transmission of disease through water and dirt. The concept of invisible contagion was later discussed by several Islamic scholars in the Ayyubid Sultanate who referred to them as najasat ("impure substances"). The fiqh scholar Ibn al-Haj al-Abdari ( c. 1250 –1336), while discussing Islamic diet and hygiene , gave warnings about how contagion can contaminate water, food, and garments, and could spread through the water supply, and may have implied contagion to be unseen particles. When the Black Death bubonic plague reached Al-Andalus in the 14th century, the Arab physicians Ibn Khatima ( c. 1369 ) and Ibn al-Khatib (1313–1374) hypothesised that infectious diseases were caused by "minute bodies" and described how they can be transmitted through garments, vessels and earrings. Ideas of contagion became more popular in Europe during the Renaissance , particularly through the writing of the Italian physician Girolamo Fracastoro . Anton van Leeuwenhoek (1632–1723) advanced the science of microscopy by being the first to observe microorganisms, allowing for easy visualization of bacteria. In the mid-19th century John Snow and William Budd did important work demonstrating the contagiousness of typhoid and cholera through contaminated water. Both are credited with decreasing epidemics of cholera in their towns by implementing measures to prevent contamination of water. Louis Pasteur proved beyond doubt that certain diseases are caused by infectious agents, and developed a vaccine for rabies . Robert Koch provided the study of infectious diseases with a scientific basis known as Koch's postulates . Edward Jenner , Jonas Salk and Albert Sabin developed effective vaccines for smallpox and polio , which would later result in the eradication and near-eradication of these diseases, respectively. Alexander Fleming discovered the world's first antibiotic , penicillin , which Florey and Chain then developed. Gerhard Domagk developed sulphonamides , the first broad spectrum synthetic antibacterial drugs. [ citation needed ] The medical treatment of infectious diseases falls into the medical field of Infectious Disease and in some cases the study of propagation pertains to the field of Epidemiology . Generally, infections are initially diagnosed by primary care physicians or internal medicine specialists. For example, an "uncomplicated" pneumonia will generally be treated by the internist or the pulmonologist (lung physician). The work of the infectious diseases specialist therefore entails working with both patients and general practitioners, as well as laboratory scientists , immunologists , bacteriologists and other specialists. [ citation needed ] An infectious disease team may be alerted when: [ citation needed ]The medical treatment of infectious diseases falls into the medical field of Infectious Disease and in some cases the study of propagation pertains to the field of Epidemiology . Generally, infections are initially diagnosed by primary care physicians or internal medicine specialists. For example, an "uncomplicated" pneumonia will generally be treated by the internist or the pulmonologist (lung physician). The work of the infectious diseases specialist therefore entails working with both patients and general practitioners, as well as laboratory scientists , immunologists , bacteriologists and other specialists. [ citation needed ] An infectious disease team may be alerted when: [ citation needed ]Several studies have reported associations between pathogen load in an area and human behavior. Higher pathogen load is associated with decreased size of ethnic and religious groups in an area. This may be due high pathogen load favoring avoidance of other groups, which may reduce pathogen transmission, or a high pathogen load preventing the creation of large settlements and armies that enforce a common culture. Higher pathogen load is also associated with more restricted sexual behavior, which may reduce pathogen transmission. It also associated with higher preferences for health and attractiveness in mates. Higher fertility rates and shorter or less parental care per child is another association that may be a compensation for the higher mortality rate. There is also an association with polygyny which may be due to higher pathogen load, making selecting males with a high genetic resistance increasingly important. Higher pathogen load is also associated with more collectivism and less individualism, which may limit contacts with outside groups and infections. There are alternative explanations for at least some of the associations although some of these explanations may in turn ultimately be due to pathogen load. Thus, polygyny may also be due to a lower male: female ratio in these areas but this may ultimately be due to male infants having increased mortality from infectious diseases. Another example is that poor socioeconomic factors may ultimately in part be due to high pathogen load preventing economic development. Evidence of infection in fossil remains is a subject of interest for paleopathologists , scientists who study occurrences of injuries and illness in extinct life forms. Signs of infection have been discovered in the bones of carnivorous dinosaurs. When present, however, these infections seem to tend to be confined to only small regions of the body. A skull attributed to the early carnivorous dinosaur Herrerasaurus ischigualastensis exhibits pit-like wounds surrounded by swollen and porous bone. The unusual texture of the bone around the wounds suggests they were affected by a short-lived, non-lethal infection. Scientists who studied the skull speculated that the bite marks were received in a fight with another Herrerasaurus . Other carnivorous dinosaurs with documented evidence of infection include Acrocanthosaurus , Allosaurus , Tyrannosaurus and a tyrannosaur from the Kirtland Formation . The infections from both tyrannosaurs were received by being bitten during a fight, like the Herrerasaurus specimen. A 2006 Space Shuttle experiment found that Salmonella typhimurium , a bacterium that can cause food poisoning , became more virulent when cultivated in space . On April 29, 2013, scientists in Rensselaer Polytechnic Institute , funded by NASA , reported that, during spaceflight on the International Space Station , microbes seem to adapt to the space environment in ways "not observed on Earth" and in ways that "can lead to increases in growth and virulence". More recently, in 2017, bacteria were found to be more resistant to antibiotics and to thrive in the near-weightlessness of space. Microorganisms have been observed to survive the vacuum of outer space.

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