The American green tree frog (Dryophytes cinereus or Hyla cinerea) is a common arboreal species of New World tree frog belonging to the family Hylidae. This nocturnal insectivore is moderately sized and has a bright green to reddish-brown coloration. Commonly found in the central and southeastern United States, the frog lives in open canopy forests and permanent waters with abundant vegetation. When defending territory, the frog either emits aggressive call signals or grapples with intruders. To avoid predation, the frog hides in its aquatic habitat.

 

Females are larger than males. Pairs breed through amplexus. Males emit low frequency advertisement calls to attract females. During mating competition, males will eavesdrop on neighboring rivals and either adjust their signal timing or remain silent to intercept call signals and mate with approaching females. Androgens energize males to vocalize.

 

The American green tree frog is moderately sized. It has long legs, a streamlined and slender build, and smooth skin. The American green tree frog ranges from 3.2 to 6.4 centimetres (1+1⁄4 to 2+1⁄2 in) in length. Their dorsum can range in color from the more common bright green to reddish-brown. Such a range in coloration may result in the frog being mistaken for other species. Some evidence suggests that green tree frogs can exhibit a color change in response to their background and/or temperature.

 

The dorsum is peppered with small golden spots, and the frogs have a white to cream coloration on their ventral side. American green tree frogs also contain white prominent lateral stripes.

 

They are normally ectothermic and heterothermic.

 

The American green tree frog weighs on average 3.76g with a range between 2.15g and 5.11g. Female frogs are usually larger than males. Larger males tend to have an upper hand in attracting females than smaller males either through increased physical strength in duels or more pronounced call signals during mating competition.

 

The American green tree frog is found in the central and southeastern United States with a geographic range from the Eastern Shore of Maryland to southeast Florida with populations as far west as central Texas and as far north as Delaware and southern New Jersey. The American green tree frog is considered monotypic, but clinal variation has beven observed from Florida north along the Atlantic coastal plain. This may be attributed to the result of strong selection and/or drift.

 

American green tree frogs prefer to live in open canopy forests and permanent waters filled with plentiful vegetation. The species is found in natural and settled environments. The species commonly resides in cypress ponds, water lily prairies, and marshes. They are often found perched on twigs, low branches, and grasses.

 

A growing number of American green tree frogs have experienced severe habitat loss primarily due to urbanization and destructive wildfires that can destroy forest canopy cover. Since most amphibians have narrow habitat tolerances and migration constraints, American green tree frogs urgently need alternative shelters for survival as forest canopies recover. In a study from Central Texas, scientists have tried to combat wildfire habitat loss by creating artificial shelters using PVC pipes.Wetlands that the American green tree frogs occupy for breeding have had an increase in salinity and an increase in pesticide concentration in recent years due to urbanization. This has proven to have a negative effect on sperm mobility and has reduced reproductive success

 

One study finds that there are at least 31 tree frog species of the genus Hyla (or Dryophytes) in North America, Central America, and Eurasia. Examples include both the H. gratiosa and H. walkeri. While many tree frogs reside in the New World, a notable number of frogs inhabit the Eurasia continent and display unique biogeographic patterns based on an analysis of nuclear and mitochondrial DNA sequences.

 

American green tree frogs will defend their mate calling sites against foreign rivals and invaders using aggressive interactions. Such behaviors include a combination of aggressive call signals and wrestling from males.

 

American green tree frogs are insectivores, primarily consuming flies, mosquitoes, grasshoppers, cockroaches, spiders, beetles, and other small insects such as crickets and ants. One study suggested frogs select prey not by their size, but according to their activity levels, with the most active prey being the most frequently eaten. The same study showed "nearly 90% of Hyla cinerea prey were actively pursued", with the other 10% being "insects walking or close enough to be snatched up by the frog's tongue". Another study showed that it is not uncommon for American green tree frogs to ingest plant material.

 

Because the species is small and easily frightened, they often does not do well with frequent handling. Some specimens do seem to tolerate it occasionally, so handling frequency should be determined on an individual basis. The American green tree frog tends to be nocturnal, so they will be most active once the lights are off. Males call most of the year, especially after being misted in their tank.

 

Most American green tree frog females breed once per year, but some have multiple clutches in a single mating season. In a Florida population, "advertisement calls of males were documented between March and September and pairs in amplexus were observed between April and August". The average number of eggs in a single clutch was observed to be about 400 for this specific population. Eggs take between 4 and 14 days to hatch, with an average of five days. According to the Animal Diversity Web at the University of Michigan Museum of Zoology, "Female size was positively correlated with clutch size, but after the initial clutch, the number of eggs nearly always decreased".

 

Tadpoles are green with a yellow or white stripe extending from each nostril to the eye and may have mottled tail fins. American green tree frogs show only the parental investment of mating and egg-laying.

 

Breeding is known to be strongly influenced by day length, temperature, and precipitation. While the influence of these factors with respect to breeding is not well understood, it is well documented, as the frogs generally breed following rainfall and males call more frequently as temperature and day length increase. Some evidence demonstrates that the length of the breeding season is correlated with latitude; seasonal length decreases as latitude increases due to temperature limitations.

 

To attract mates, the male American green tree frog uses a distinctive advertisement call which is noticeably different from its release or warning calls.[citation needed] This is important for reproductive isolation in areas where different species share breeding areas. Once a mate has been attracted, the pair begins amplexus in which the male frog grasps onto the female to initiate fertilization. The species is polygynous, with the male generally seeking to mate with as many females as it can attract. Eggs are attached to substrates such as emergent vegetation, and unlike other frog species, these egg masses are typically laid in permanent bodies of water rather than vernal pools.

 

When male frogs aggregate, choruses will form and establish a cacophony of numerous unique advertisement calls. Consequently, male individuals experience intraspecific mating competition and often encounter immense pressure to produce unique call signals that are both attractive and audible to the limited number of available females. Such challenges are further complicated by the rapid fluctuation of males within a chorus, the potential risk of increased exposure to predators, and sexual selection of specific call signals through female choice.

 

These factors give rise to a social plasticity in the calling behavior of the American green tree frog. In order to maintain competition, male individuals will either modify their signal features, such as the temporal and spectral properties of calls or their signal timing, to reduce signal interference with other neighboring males. Temporal and spectral properties include call duration and call frequency. Changes in signal timing include initiation of advertisement calls during different times of the night. It has been found that male green tree frogs will more often alter their signal timing to attract females due to physiological constraints in the frog's call production mechanism and female choice against increased call duration and period in favor of precise call timing. Modifying signal behavior towards every frog within a chorus is extremely costly and inefficient. However, forcing male individuals to engage in selective attention of advertisement calls from only a few of their closest rivals.

 

Some male American green tree frogs will not emit or alter their advertisement calls and instead choose to remain silent. Labeled as 'satellites', these frogs will wait to intercept the signals of nearby calling males and mate with approaching sexually active females through amplexus. Such sexual parasitism and call avoidance occur mainly to conserve the frog's energy and avoid predation during mate competition.

 

Androgens are used for energy during call signal production. As a satellite male green tree frog engages in non-calling mating behavior, androgen quantities are found to decrease to lower levels compared to calling behavior, suggesting a causal relationship between sex hormones and mate calling tactics.

 

In order to help decide whether to engage in satellite non-calling behavior, male green tree frogs will eavesdrop on other nearby male competitors and adjust their mating responses based on the qualities of their call signals. If given with the choice, females prefer large males with advertisement calls of lower frequencies. Other notable features include the latency to call and male focal size. When eavesdropping male competitors with low call frequencies, large male green tree frogs are found to reduce their latency to call and raise call rates. Small males in contrast will only reduce their latency to call in response to competitors with average call frequencies.

 

American green tree frogs are also able to undergo interspecific mating competition. In southern Florida, the Cuban tree frog (Osteopilus septentrionalis) is an invasive species that has a similar call to the American green tree frog with respect to timing and pitch. A study found that their calls compete acoustically with each other due to their similarity which limits communication space. In order to compete with the Cuban tree frog, American green tree frogs modified their calls to be shorter, louder, and more frequent so that potential mates would have a better chance of detecting the call.

 

As a tadpole, the American green tree frog is easily predated by sunfish, bass, and dragonflies, including both aeshnidae and libellulidae odonate naiads. The species is especially vulnerable to predation when living in temporary ponds compared to permanent waters. To combat predation, green tree frog tadpoles may increase hiding behavior while in water to avoid capture.

 

The American green tree frog is also prone to a few parasites, including nematodes, protozoans, and trematodes.

 

Contrary to most amphibians, the American green tree frog is not easily susceptible to the Batrachochytrium dendrobatidis (Bd) pathogen and the disease chytridiomycosis. Reasons explaining why are relatively unknown, but one study hypothesizes that variances in climate, frog immunity, and frog habitat are potential factors.

 

Androgens, such as dihydrotestosterone and testosterone, are the primary energy resource for American green tree frogs when engaging in acoustic signal calling. When a male frog engages in vocalization either for aggression or mate attraction, androgen energy stores are used and become depleted. Interestingly, glucocorticoids, such as corticosterones, also appear to change during calling behavior. According to the Energetics-Hormone Vocalization model, glucocorticoid levels in males will rise as androgen levels decrease following vocalization. When observing hormonal levels in both calling and satellite non-calling males, reduced androgen levels and elevated glucocorticoid levels are found among satellite non-calling males compared to calling males. These observations suggest a possible mechanism dictating vocalization and the alternation between calling and non-calling behavior in the green tree frog. Further study is required however on the relationship between glucocorticoids and male vocalization to consider causality.

 

The causality of vocalization by androgens is also limited by the American green tree frog's social environment. According to one study, androgens themselves were not sufficient to initiate call signals in male frogs when in the presence of social stimuli such as other frog choruses. This suggests that androgens on their own may provide males with enough motivation to call, but they may also require additional social context to produce various call signals during situations such as mating.

 

American green tree frogs are popular pets because of their small size, appearance, and the undemanding conditions needed to take care of them. Unlike many amphibians, they do not require artificial heating unless household temperatures drop below 21 °C (70 °F). They need a large (at least ten-gallon) terrarium and do best with a substrate that will hold some humidity, such as commercial shredded bark or coconut husk bedding, or untreated topsoil on the floor of the terrarium. Tree frogs are arboreal, so the height of the tank is more important than the length. A variety of things for climbing, such as plants or branches, should be in the habitat. A shallow water dish should be included. Captive frogs should not be handled more than necessary; when necessary, clean gloves should be worn.

 

The American green tree frog became the state amphibian of Louisiana in 1997 and of Georgia in 2005.

 

American green tree frogs can also be used as bioindicators for aquatic contamination. Synthetic compounds such as polychlorinated biphenyls are found in many pesticides and pollute the green tree frog's aquatic habitats. Because the frog's skin is thin and permeable, synthetic compounds absorb easily upon contact, making the species a viable variable to measure contamination

The American green tree frog (Dryophytes cinereus or Hyla cinerea) is a common arboreal species of New World tree frog belonging to the family Hylidae. This nocturnal insectivore is moderately sized and has a bright green to reddish-brown coloration. Commonly found in the central and southeastern United States, the frog lives in open canopy forests and permanent waters with abundant vegetation. When defending territory, the frog either emits aggressive call signals or grapples with intruders. To avoid predation, the frog hides in its aquatic habitat.

 

Females are larger than males. Pairs breed through amplexus. Males emit low frequency advertisement calls to attract females. During mating competition, males will eavesdrop on neighboring rivals and either adjust their signal timing or remain silent to intercept call signals and mate with approaching females. Androgens energize males to vocalize.

 

Description

 

The American green tree frog is moderately sized. It has long legs, a streamlined and slender build, and smooth skin. The American green tree frog ranges from 3.2 to 6.4 centimetres (1+1⁄4 to 2+1⁄2 in) in length. Their dorsum can range in color from the more common bright green to reddish-brown. Such a range in coloration may result in the frog being mistaken for other species. Some evidence suggests that green tree frogs can exhibit a color change in response to their background and/or temperature.

 

The dorsum is peppered with small golden spots, and the frogs have a white to cream coloration on their ventral side. American green tree frogs also contain white prominent lateral stripes.

 

They are normally ectothermic and heterothermic.

 

The American green tree frog weighs on average 3.76g with a range between 2.15g and 5.11g. Female frogs are usually larger than males. Larger males tend to have an upper hand in attracting females than smaller males either through increased physical strength in duels or more pronounced call signals during mating competition.

 

Distribution and habitat

The American green tree frog is found in the central and southeastern United States with a geographic range from the Eastern Shore of Maryland to southeast Florida with populations as far west as central Texas and as far north as Delaware and southern New Jersey. The American green tree frog is considered monotypic, but clinal variation has beven observed from Florida north along the Atlantic coastal plain. This may be attributed to the result of strong selection and/or drift.

 

American green tree frogs prefer to live in open canopy forests and permanent waters filled with plentiful vegetation. The species is found in natural and settled environments. The species commonly resides in cypress ponds, water lily prairies, and marshes. They are often found perched on twigs, low branches, and grasses.

 

Conservation

A growing number of American green tree frogs have experienced severe habitat loss primarily due to urbanization and destructive wildfires that can destroy forest canopy cover. Since most amphibians have narrow habitat tolerances and migration constraints, American green tree frogs urgently need alternative shelters for survival as forest canopies recover. In a study from Central Texas, scientists have tried to combat wildfire habitat loss by creating artificial shelters using PVC pipes.Wetlands that the American green tree frogs occupy for breeding have had an increase in salinity and an increase in pesticide concentration in recent years due to urbanization. This has proven to have a negative effect on sperm mobility and has reduced reproductive success

 

Population structure, speciation, and phylogeny

One study finds that there are at least 31 tree frog species of the genus Hyla (or Dryophytes) in North America, Central America, and Eurasia. Examples include both the H. gratiosa and H. walkeri. While many tree frogs reside in the New World, a notable number of frogs inhabit the Eurasia continent and display unique biogeographic patterns based on an analysis of nuclear and mitochondrial DNA sequences.

 

Home range and territoriality

American green tree frogs will defend their mate calling sites against foreign rivals and invaders using aggressive interactions. Such behaviors include a combination of aggressive call signals and wrestling from males.

 

Diet

American green tree frogs are insectivores, primarily consuming flies, mosquitoes, grasshoppers, cockroaches, spiders, beetles, and other small insects such as crickets and ants. One study suggested frogs select prey not by their size, but according to their activity levels, with the most active prey being the most frequently eaten. The same study showed "nearly 90% of Hyla cinerea prey were actively pursued", with the other 10% being "insects walking or close enough to be snatched up by the frog's tongue". Another study showed that it is not uncommon for American green tree frogs to ingest plant material.

 

Behavior

 

Because the species is small and easily frightened, they often does not do well with frequent handling. Some specimens do seem to tolerate it occasionally, so handling frequency should be determined on an individual basis. The American green tree frog tends to be nocturnal, so they will be most active once the lights are off. Males call most of the year, especially after being misted in their tank.

 

Breeding

Pair breeding

 

Most American green tree frog females breed once per year, but some have multiple clutches in a single mating season. In a Florida population, "advertisement calls of males were documented between March and September and pairs in amplexus were observed between April and August". The average number of eggs in a single clutch was observed to be about 400 for this specific population. Eggs take between 4 and 14 days to hatch, with an average of five days. According to the Animal Diversity Web at the University of Michigan Museum of Zoology, "Female size was positively correlated with clutch size, but after the initial clutch, the number of eggs nearly always decreased".

 

Tadpoles are green with a yellow or white stripe extending from each nostril to the eye and may have mottled tail fins. American green tree frogs show only the parental investment of mating and egg-laying.

 

Breeding is known to be strongly influenced by day length, temperature, and precipitation. While the influence of these factors with respect to breeding is not well understood, it is well documented, as the frogs generally breed following rainfall and males call more frequently as temperature and day length increase. Some evidence demonstrates that the length of the breeding season is correlated with latitude; seasonal length decreases as latitude increases due to temperature limitations.

 

Mating calls

To attract mates, the male American green tree frog uses a distinctive advertisement call which is noticeably different from its release or warning calls.[citation needed] This is important for reproductive isolation in areas where different species share breeding areas. Once a mate has been attracted, the pair begins amplexus in which the male frog grasps onto the female to initiate fertilization. The species is polygynous, with the male generally seeking to mate with as many females as it can attract. Eggs are attached to substrates such as emergent vegetation, and unlike other frog species, these egg masses are typically laid in permanent bodies of water rather than vernal pools.

 

When male frogs aggregate, choruses will form and establish a cacophony of numerous unique advertisement calls. Consequently, male individuals experience intraspecific mating competition and often encounter immense pressure to produce unique call signals that are both attractive and audible to the limited number of available females. Such challenges are further complicated by the rapid fluctuation of males within a chorus, the potential risk of increased exposure to predators, and sexual selection of specific call signals through female choice.

 

These factors give rise to a social plasticity in the calling behavior of the American green tree frog. In order to maintain competition, male individuals will either modify their signal features, such as the temporal and spectral properties of calls or their signal timing, to reduce signal interference with other neighboring males. Temporal and spectral properties include call duration and call frequency. Changes in signal timing include initiation of advertisement calls during different times of the night. It has been found that male green tree frogs will more often alter their signal timing to attract females due to physiological constraints in the frog's call production mechanism and female choice against increased call duration and period in favor of precise call timing. Modifying signal behavior towards every frog within a chorus is extremely costly and inefficient. However, forcing male individuals to engage in selective attention of advertisement calls from only a few of their closest rivals.

 

Satellite males

Some male American green tree frogs will not emit or alter their advertisement calls and instead choose to remain silent. Labeled as 'satellites', these frogs will wait to intercept the signals of nearby calling males and mate with approaching sexually active females through amplexus. Such sexual parasitism and call avoidance occur mainly to conserve the frog's energy and avoid predation during mate competition.

 

Androgens are used for energy during call signal production. As a satellite male green tree frog engages in non-calling mating behavior, androgen quantities are found to decrease to lower levels compared to calling behavior, suggesting a causal relationship between sex hormones and mate calling tactics.

 

In order to help decide whether to engage in satellite non-calling behavior, male green tree frogs will eavesdrop on other nearby male competitors and adjust their mating responses based on the qualities of their call signals. If given with the choice, females prefer large males with advertisement calls of lower frequencies. Other notable features include the latency to call and male focal size. When eavesdropping male competitors with low call frequencies, large male green tree frogs are found to reduce their latency to call and raise call rates. Small males in contrast will only reduce their latency to call in response to competitors with average call frequencies.

 

Interspecific competition

American green tree frogs are also able to undergo interspecific mating competition. In southern Florida, the Cuban tree frog (Osteopilus septentrionalis) is an invasive species that has a similar call to the American green tree frog with respect to timing and pitch. A study found that their calls compete acoustically with each other due to their similarity which limits communication space. In order to compete with the Cuban tree frog, American green tree frogs modified their calls to be shorter, louder, and more frequent so that potential mates would have a better chance of detecting the call.

 

Threats

As a tadpole, the American green tree frog is easily predated by sunfish, bass, and dragonflies, including both aeshnidae and libellulidae odonate naiads. The species is especially vulnerable to predation when living in temporary ponds compared to permanent waters. To combat predation, green tree frog tadpoles may increase hiding behavior while in water to avoid capture.

 

The American green tree frog is also prone to a few parasites, including nematodes, protozoans, and trematodes.

 

Contrary to most amphibians, the American green tree frog is not easily susceptible to the Batrachochytrium dendrobatidis (Bd) pathogen and the disease chytridiomycosis. Reasons explaining why are relatively unknown, but one study hypothesizes that variances in climate, frog immunity, and frog habitat are potential factors.

 

Physiology

Androgens

Androgens, such as dihydrotestosterone and testosterone, are the primary energy resource for American green tree frogs when engaging in acoustic signal calling. When a male frog engages in vocalization either for aggression or mate attraction, androgen energy stores are used and become depleted. Interestingly, glucocorticoids, such as corticosterones, also appear to change during calling behavior. According to the Energetics-Hormone Vocalization model, glucocorticoid levels in males will rise as androgen levels decrease following vocalization. When observing hormonal levels in both calling and satellite non-calling males, reduced androgen levels and elevated glucocorticoid levels are found among satellite non-calling males compared to calling males. These observations suggest a possible mechanism dictating vocalization and the alternation between calling and non-calling behavior in the green tree frog. Further study is required however on the relationship between glucocorticoids and male vocalization to consider causality.

 

The causality of vocalization by androgens is also limited by the American green tree frog's social environment. According to one study, androgens themselves were not sufficient to initiate call signals in male frogs when in the presence of social stimuli such as other frog choruses. This suggests that androgens on their own may provide males with enough motivation to call, but they may also require additional social context to produce various call signals during situations such as mating.

 

As pets

American green tree frogs are popular pets because of their small size, appearance, and the undemanding conditions needed to take care of them. Unlike many amphibians, they do not require artificial heating unless household temperatures drop below 21 °C (70 °F). They need a large (at least ten-gallon) terrarium and do best with a substrate that will hold some humidity, such as commercial shredded bark or coconut husk bedding, or untreated topsoil on the floor of the terrarium. Tree frogs are arboreal, so the height of the tank is more important than the length. A variety of things for climbing, such as plants or branches, should be in the habitat. A shallow water dish should be included. Captive frogs should not be handled more than necessary; when necessary, clean gloves should be worn.

 

As state symbols and bioindicators

The American green tree frog became the state amphibian of Louisiana in 1997 and of Georgia in 2005.

 

American green tree frogs can also be used as bioindicators for aquatic contamination. Synthetic compounds such as polychlorinated biphenyls are found in many pesticides and pollute the green tree frog's aquatic habitats. Because the frog's skin is thin and permeable, synthetic compounds absorb easily upon contact, making the species a viable variable to measure contamination

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic.

 

Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. Of those people who develop noticeable symptoms, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging), and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). Older people are more likely to have severe symptoms. At least a third of the people who are infected with the virus remain asymptomatic and do not develop noticeable symptoms at any point in time, but they still can spread the disease.[ Around 20% of those people will remain asymptomatic throughout infection, and the rest will develop symptoms later on, becoming pre-symptomatic rather than asymptomatic and therefore having a higher risk of transmitting the virus to others. Some people continue to experience a range of effects—known as long COVID—for months after recovery, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

The virus that causes COVID-19 spreads mainly when an infected person is in close contact[a] with another person. Small droplets and aerosols containing the virus can spread from an infected person's nose and mouth as they breathe, cough, sneeze, sing, or speak. Other people are infected if the virus gets into their mouth, nose or eyes. The virus may also spread via contaminated surfaces, although this is not thought to be the main route of transmission. The exact route of transmission is rarely proven conclusively, but infection mainly happens when people are near each other for long enough. People who are infected can transmit the virus to another person up to two days before they themselves show symptoms, as can people who do not experience symptoms. People remain infectious for up to ten days after the onset of symptoms in moderate cases and up to 20 days in severe cases. Several testing methods have been developed to diagnose the disease. The standard diagnostic method is by detection of the virus' nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

 

Preventive measures include physical or social distancing, quarantining, ventilation of indoor spaces, covering coughs and sneezes, hand washing, and keeping unwashed hands away from the face. The use of face masks or coverings has been recommended in public settings to minimise the risk of transmissions. Several vaccines have been developed and several countries have initiated mass vaccination campaigns.

 

Although work is underway to develop drugs that inhibit the virus, the primary treatment is currently symptomatic. Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.

 

SIGNS AND SYSTOMS

Symptoms of COVID-19 are variable, ranging from mild symptoms to severe illness. Common symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, and breathing difficulties. People with the same infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, and throat disorders, loss of taste combined with loss of smell is associated with COVID-19.

 

Most people (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) and 5% of patients suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can spread the disease. Other infected people will develop symptoms later, called "pre-symptomatic", or have very mild symptoms and can also spread the virus.

 

As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.

Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects for months after recovery—named long COVID—and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

CAUSE

TRANSMISSION

Coronavirus disease 2019 (COVID-19) spreads from person to person mainly through the respiratory route after an infected person coughs, sneezes, sings, talks or breathes. A new infection occurs when virus-containing particles exhaled by an infected person, either respiratory droplets or aerosols, get into the mouth, nose, or eyes of other people who are in close contact with the infected person. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection.

 

The closer people interact, and the longer they interact, the more likely they are to transmit COVID-19. Closer distances can involve larger droplets (which fall to the ground) and aerosols, whereas longer distances only involve aerosols. Larger droplets can also turn into aerosols (known as droplet nuclei) through evaporation. The relative importance of the larger droplets and the aerosols is not clear as of November 2020; however, the virus is not known to spread between rooms over long distances such as through air ducts. Airborne transmission is able to particularly occur indoors, in high risk locations such as restaurants, choirs, gyms, nightclubs, offices, and religious venues, often when they are crowded or less ventilated. It also occurs in healthcare settings, often when aerosol-generating medical procedures are performed on COVID-19 patients.

 

Although it is considered possible there is no direct evidence of the virus being transmitted by skin to skin contact. A person could get COVID-19 indirectly by touching a contaminated surface or object before touching their own mouth, nose, or eyes, though this is not thought to be the main way the virus spreads. The virus is not known to spread through feces, urine, breast milk, food, wastewater, drinking water, or via animal disease vectors (although some animals can contract the virus from humans). It very rarely transmits from mother to baby during pregnancy.

 

Social distancing and the wearing of cloth face masks, surgical masks, respirators, or other face coverings are controls for droplet transmission. Transmission may be decreased indoors with well maintained heating and ventilation systems to maintain good air circulation and increase the use of outdoor air.

 

The number of people generally infected by one infected person varies. Coronavirus disease 2019 is more infectious than influenza, but less so than measles. It often spreads in clusters, where infections can be traced back to an index case or geographical location. There is a major role of "super-spreading events", where many people are infected by one person.

 

A person who is infected can transmit the virus to others up to two days before they themselves show symptoms, and even if symptoms never appear. People remain infectious in moderate cases for 7–12 days, and up to two weeks in severe cases. In October 2020, medical scientists reported evidence of reinfection in one person.

 

VIROLOGY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature.

 

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.

 

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have an animal (zoonotic) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The structure of the M protein resembles the sugar transporter SemiSWEET.

 

The many thousands of SARS-CoV-2 variants are grouped into clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR).

 

Several notable variants of SARS-CoV-2 emerged in late 2020. Cluster 5 emerged among minks and mink farmers in Denmark. After strict quarantines and a mink euthanasia campaign, it is believed to have been eradicated. The Variant of Concern 202012/01 (VOC 202012/01) is believed to have emerged in the United Kingdom in September. The 501Y.V2 Variant, which has the same N501Y mutation, arose independently in South Africa.

 

SARS-CoV-2 VARIANTS

Three known variants of SARS-CoV-2 are currently spreading among global populations as of January 2021 including the UK Variant (referred to as B.1.1.7) first found in London and Kent, a variant discovered in South Africa (referred to as 1.351), and a variant discovered in Brazil (referred to as P.1).

 

Using Whole Genome Sequencing, epidemiology and modelling suggest the new UK variant ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020) transmits more easily than other strains.

 

PATHOPHYSIOLOGY

COVID-19 can affect the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective. As the alveolar disease progresses, respiratory failure might develop and death may follow.

 

Whether SARS-CoV-2 is able to invade the nervous system remains unknown. The virus is not detected in the CNS of the majority of COVID-19 people with neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID-19, but these results need to be confirmed. SARS-CoV-2 could cause respiratory failure through affecting the brain stem as other coronaviruses have been found to invade the CNS. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood-brain barrier to gain access to the CNS, possibly within an infected white blood cell.

 

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

 

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism have been found people transferred to Intensive care unit (ICU) with COVID-19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in people infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia. Furthermore, microvascular blood vessel damage has been reported in a small number of tissue samples of the brains – without detected SARS-CoV-2 – and the olfactory bulbs from those who have died from COVID-19.

 

Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of hospitalized patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

 

Autopsies of people who died of COVID-19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.

 

IMMUNOPATHOLOGY

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID-19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.

 

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

 

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID-19 . Lymphocytic infiltrates have also been reported at autopsy.

 

VIRAL AND HOST FACTORS

VIRUS PROTEINS

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus host range and cellular tropism via the receptor binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID-19 vaccines.

 

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response.

 

HOST FACTORS

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-COV2 virus targets causing COVID-19. Theoretically the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID-19, though animal data suggest some potential protective effect of ARB. However no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.

 

The virus' effect on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome.

 

HOST CYTOKINE RESPONSE

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm. Levels of interleukin 1B, interferon-gamma, interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID-19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID-19 disease.

 

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID-19, it is related to worse prognosis and increased fatality. The storm causes the acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis, acute kidney injury, and vasculitis. The production of IL-1, IL-2, IL-6, TNF-alpha, and interferon-gamma, all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system, the microglia, neurons, and astrocytes, are also be involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.

 

DIAGNOSIS

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.

 

VIRAL TESTING

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests, which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited." The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease.

 

A number of laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK.

 

The University of Oxford's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" On 7 September, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results."

 

IMAGING

Chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.

 

Many groups have created COVID-19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID-19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive.

Coding

In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.

 

PATHOLOGY

The main pathological findings at autopsy are:

 

Macroscopy: pericarditis, lung consolidation and pulmonary oedema

Lung findings:

minor serous exudation, minor fibrin exudation

pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation

diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

plasmocytosis in BAL

Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

Liver: microvesicular steatosis

 

PREVENTION

Preventive measures to reduce the chances of infection include staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.

 

Those diagnosed with COVID-19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.

 

The first COVID-19 vaccine was granted regulatory approval on 2 December by the UK medicines regulator MHRA. It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID-19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID-19 is trying to decrease and delay the epidemic peak, known as "flattening the curve". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.

 

VACCINE

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus causing coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which enabled accelerated development of various vaccine technologies during early 2020. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19.

 

In Phase III trials, several COVID‑19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of March 2021, 12 vaccines were authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, and CoviVac), four viral vector vaccines (Sputnik V, the Oxford–AstraZeneca vaccine, Convidicea, and the Johnson & Johnson vaccine), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer). In total, as of March 2021, 308 vaccine candidates were in various stages of development, with 73 in clinical research, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development.

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. As of 17 March 2021, 400.22 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses, and Sputnik V, Sinopharm, Sinovac, and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. 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.

 

SOCIAL DISTANCING

Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. Many governments are now mandating or recommending social distancing in regions affected by the outbreak.

 

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.

 

SELF-ISOLATION

Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.

Face masks and respiratory hygiene

 

The WHO and the US CDC recommend individuals wear non-medical face coverings in public settings where there is an increased risk of transmission and where social distancing measures are difficult to maintain. This recommendation is meant to reduce the spread of the disease by asymptomatic and pre-symptomatic individuals and is complementary to established preventive measures such as social distancing. Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing. A face covering without vents or holes will also filter out particles containing the virus from inhaled and exhaled air, reducing the chances of infection. But, if the mask include an exhalation valve, a wearer that is infected (maybe without having noticed that, and asymptomatic) would transmit the virus outwards through it, despite any certification they can have. So the masks with exhalation valve are not for the infected wearers, and are not reliable to stop the pandemic in a large scale. Many countries and local jurisdictions encourage or mandate the use of face masks or cloth face coverings by members of the public to limit the spread of the virus.

 

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease. When not wearing a mask, the CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. Healthcare professionals interacting directly with people who have COVID-19 are advised to use respirators at least as protective as NIOSH-certified N95 or equivalent, in addition to other personal protective equipment.

 

HAND-WASHING AND HYGIENE

Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. The CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

 

SURFACE CLEANING

After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body cause infection. Current evidence indicates that contact with infected surfaces is not the main driver of Covid-19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticized as hygiene theater, giving a false sense of security against something primarily spread through the air.

 

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight. Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%).

 

On many surfaces, including as glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. As a general rule of thumb, the virus dies faster on porous surfaces than on non-porous surfaces.

However, this rule is not absolute, and of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces.

 

Surfaces may be decontaminated with 62–71 percent ethanol, 50–100 percent isopropanol, 0.1 percent sodium hypochlorite, 0.5 percent hydrogen peroxide, and 0.2–7.5 percent povidone-iodine. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used. The CDC recommends that if a COVID-19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons should be disinfected. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inocuylum volumes) can be seen in the supplementary material of.

 

VENTILATION AND AIR FILTRATION

The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.

 

HEALTHY DIET AND LIFESTYLE

The Harvard T.H. Chan School of Public Health recommends a healthy diet, being physically active, managing psychological stress, and getting enough sleep.

 

While there is no evidence that vitamin D is an effective treatment for COVID-19, there is limited evidence that vitamin D deficiency increases the risk of severe COVID-19 symptoms. This has led to recommendations for individuals with vitamin D deficiency to take vitamin D supplements as a way of mitigating the risk of COVID-19 and other health issues associated with a possible increase in deficiency due to social distancing.

 

TREATMENT

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. Thus, the cornerstone of management of COVID-19 is supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

 

Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.

 

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.

Several experimental treatments are being actively studied in clinical trials. Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful. Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment. Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy.

 

PROGNOSIS

The severity of COVID-19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalization. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID-19 and with a transfer to ICU.

 

Some early studies suggest 10% to 20% of people with COVID-19 will experience symptoms lasting longer than a month.[191][192] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020 WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID-19 symptoms that fluctuate over time as "really concerning." They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros has concluded that therefore herd immunity is "morally unconscionable and unfeasible".

 

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within 2 months of discharge. The average to readmit was 8 days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease.

 

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers, air pollution is similarly associated with risk factors, and pre-existing heart and lung diseases and also obesity contributes to an increased health risk of COVID-19.

 

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research that looked into the COVID-19 infections in hospitalized kidney transplant recipients found a mortality rate of 11%.

See also: Impact of the COVID-19 pandemic on children

 

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years. They are likely to have milder symptoms and a lower chance of severe disease than adults. A European multinational study of hospitalized children published in The Lancet on 25 June 2020 found that about 8% of children admitted to a hospital needed intensive care. Four of those 582 children (0.7%) died, but the actual mortality rate could be "substantially lower" since milder cases that did not seek medical help were not included in the study.

 

Genetics also plays an important role in the ability to fight off the disease. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID-19. Genetic screening is able to detect interferon effector genes.

 

Pregnant women may be at higher risk of severe COVID-19 infection based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.

 

COMPLICATIONS

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death. Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots. Approximately 20–30% of people who present with COVID-19 have elevated liver enzymes, reflecting liver injury.

 

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions). Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID-19 and have an altered mental status.

 

LONGER-TERM EFFECTS

Some early studies suggest that that 10 to 20% of people with COVID-19 will experience symptoms lasting longer than a month. A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath. About 5-10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.

 

By a variety of mechanisms, the lungs are the organs most affected in COVID-19.[228] The majority of CT scans performed show lung abnormalities in people tested after 28 days of illness.

 

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long lasting effects, including pulmonary fibrosis. Overall, approximately one third of those investigated after 4 weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in people who are asymptomatic, but with the suggestion of continuing improvement with the passing of more time.

 

IMMUNITY

The immune response by humans to CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralizing antibodies in blood strongly correlates with protection from infection, but the level of neutralizing antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralizing antibody two months after infection. In another study, the level of neutralizing antibody fell 4-fold 1 to 4 months after the onset of symptoms. However, the lack of antibody in the blood does not mean antibody will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least 6 months after appearance of symptoms. Nevertheless, 15 cases of reinfection with SARS-CoV-2 have been reported using stringent CDC criteria requiring identification of a different variant from the second infection. There are likely to be many more people who have been reinfected with the virus. Herd immunity will not eliminate the virus if reinfection is common. Some other coronaviruses circulating in people are capable of reinfection after roughly a year. Nonetheless, on 3 March 2021, scientists reported that a much more contagious Covid-19 variant, Lineage P.1, first detected in Japan, and subsequently found in Brazil, as well as in several places in the United States, may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.

 

MORTALITY

Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly.

 

The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 2.2% (2,685,770/121,585,388) as of 18 March 2021. The number varies by region. The CFR may not reflect the true severity of the disease, because some infected individuals remain asymptomatic or experience only mild symptoms, and hence such infections may not be included in official case reports. Moreover, the CFR may vary markedly over time and across locations due to the availability of live virus tests.

 

INFECTION FATALITY RATE

A key metric in gauging the severity of COVID-19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk. This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR, the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases.

 

CURRENT ESTIMATES

A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO.

 

EARLIER ESTIMATES OF IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.[ On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID-19 (0.3% of the population).Antibody testing in New York City suggested an IFR of ~0.9%,[258] and ~1.4%. In Bergamo province, 0.6% of the population has died. In September 2020 the U.S. Center for Disease Control & Prevention reported preliminary estimates of age-specific IFRs for public health planning purposes.

 

SEX DIFFERENCES

Early reviews of epidemiologic data showed gendered impact of the pandemic and a higher mortality rate in men in China and Italy. The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected people were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.

 

ETHNIC DIFFERENCES

In the US, a greater proportion of deaths due to COVID-19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the U.K., a greater proportion of deaths due to COVID-19 have occurred in those of a Black, Asian, and other ethnic minority background. More severe impacts upon victims including the relative incidence of the necessity of hospitalization requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet. This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe.

 

COMORBIDITIES

Most of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease. According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), Ischemic Heart Disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths).

 

Most critical respiratory comorbidities according to the CDC, are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis. Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms. COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.

 

In August 2020 the CDC issued a caution that tuberculosis infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID-19 couldn't rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB related deaths by 2025.

 

NAME

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu, Middle East Respiratory Syndrome, and Zika virus. In January 2020, the WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species, or groups of people in disease and virus names in part to prevent social stigma. The official names COVID-19 and SARS-CoV-2 were issued by the WHO on 11 February 2020. Tedros Adhanom explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.

 

HISTORY

The virus is thought to be natural and of an animal origin, through spillover infection. There are several theories about where the first case (the so-called patient zero) originated. Phylogenetics estimates that SARS-CoV-2 arose in October or November 2019. Evidence suggests that it descends from a coronavirus that infects wild bats, and spread to humans through an intermediary wildlife host.

 

The first known human infections were in Wuhan, Hubei, China. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as 1 December 2019.Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals. In May 2020 George Gao, the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event, but that it was not the site of the initial outbreak.[ Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.

 

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of coronavirus cases in Hubei gradually increased, reaching 60 by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS, causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.

 

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases—enough to trigger an investigation.

 

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen. Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared the coronavirus a Public Health Emergency of International Concern. By this time, the outbreak spread by a factor of 100 to 200 times.

 

Italy had its first confirmed cases on 31 January 2020, two tourists from China. As of 13 March 2020 the WHO considered Europe the active centre of the pandemic. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020.

 

After 55 days without a locally transmitted case, Beijing reported a new COVID-19 case on 11 June 2020 which was followed by two more cases on 12 June. By 15 June there were 79 cases officially confirmed, most of them were people that went to Xinfadi Wholesale Market.

 

RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID-19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December.

 

MISINFORMATION

After the initial outbreak of COVID-19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online.

 

In September 2020, the U.S. CDC published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.

 

OTHER ANIMALS

Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis.

 

Some pets, especially cats and ferrets, can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviors which increase the risk of transmission include kissing, licking, and petting the animal.

 

The virus does not appear to be able to infect pigs, ducks, or chickens at all.[ Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.

 

Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID-19 virus.

 

Minks, which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms. Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations. A vaccine for mink and other animals is being researched.

 

RESEARCH

International research on vaccines and medicines in COVID-19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.

 

As of December 2020, hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica. As of November 2020, more than 200 possible treatments had been studied in humans so far.

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on epidemiological models, estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID-19 including computational fluid dynamics models to study the flow physics of COVID-19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID-19 on organizations worldwide.

 

TREATMENT-RELATED RESEARCH

Repurposed antiviral drugs make up most of the research into COVID-19 treatments. Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.

 

In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs, lopinavir/ritonavir; and interferon-beta. More than 300 active clinical trials were underway as of April 2020.

 

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020, France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID-19 treatment.

 

In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID-19 who do not require supplemental oxygen.

 

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID-19 patients.

 

WIKIPEDIA

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic.

 

Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. Of those people who develop noticeable symptoms, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging), and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). Older people are more likely to have severe symptoms. At least a third of the people who are infected with the virus remain asymptomatic and do not develop noticeable symptoms at any point in time, but they still can spread the disease.[ Around 20% of those people will remain asymptomatic throughout infection, and the rest will develop symptoms later on, becoming pre-symptomatic rather than asymptomatic and therefore having a higher risk of transmitting the virus to others. Some people continue to experience a range of effects—known as long COVID—for months after recovery, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

The virus that causes COVID-19 spreads mainly when an infected person is in close contact[a] with another person. Small droplets and aerosols containing the virus can spread from an infected person's nose and mouth as they breathe, cough, sneeze, sing, or speak. Other people are infected if the virus gets into their mouth, nose or eyes. The virus may also spread via contaminated surfaces, although this is not thought to be the main route of transmission. The exact route of transmission is rarely proven conclusively, but infection mainly happens when people are near each other for long enough. People who are infected can transmit the virus to another person up to two days before they themselves show symptoms, as can people who do not experience symptoms. People remain infectious for up to ten days after the onset of symptoms in moderate cases and up to 20 days in severe cases. Several testing methods have been developed to diagnose the disease. The standard diagnostic method is by detection of the virus' nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

 

Preventive measures include physical or social distancing, quarantining, ventilation of indoor spaces, covering coughs and sneezes, hand washing, and keeping unwashed hands away from the face. The use of face masks or coverings has been recommended in public settings to minimise the risk of transmissions. Several vaccines have been developed and several countries have initiated mass vaccination campaigns.

 

Although work is underway to develop drugs that inhibit the virus, the primary treatment is currently symptomatic. Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.

 

SIGNS AND SYSTOMS

Symptoms of COVID-19 are variable, ranging from mild symptoms to severe illness. Common symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, and breathing difficulties. People with the same infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, and throat disorders, loss of taste combined with loss of smell is associated with COVID-19.

 

Most people (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) and 5% of patients suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can spread the disease. Other infected people will develop symptoms later, called "pre-symptomatic", or have very mild symptoms and can also spread the virus.

 

As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.

Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects for months after recovery—named long COVID—and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

CAUSE

TRANSMISSION

Coronavirus disease 2019 (COVID-19) spreads from person to person mainly through the respiratory route after an infected person coughs, sneezes, sings, talks or breathes. A new infection occurs when virus-containing particles exhaled by an infected person, either respiratory droplets or aerosols, get into the mouth, nose, or eyes of other people who are in close contact with the infected person. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection.

 

The closer people interact, and the longer they interact, the more likely they are to transmit COVID-19. Closer distances can involve larger droplets (which fall to the ground) and aerosols, whereas longer distances only involve aerosols. Larger droplets can also turn into aerosols (known as droplet nuclei) through evaporation. The relative importance of the larger droplets and the aerosols is not clear as of November 2020; however, the virus is not known to spread between rooms over long distances such as through air ducts. Airborne transmission is able to particularly occur indoors, in high risk locations such as restaurants, choirs, gyms, nightclubs, offices, and religious venues, often when they are crowded or less ventilated. It also occurs in healthcare settings, often when aerosol-generating medical procedures are performed on COVID-19 patients.

 

Although it is considered possible there is no direct evidence of the virus being transmitted by skin to skin contact. A person could get COVID-19 indirectly by touching a contaminated surface or object before touching their own mouth, nose, or eyes, though this is not thought to be the main way the virus spreads. The virus is not known to spread through feces, urine, breast milk, food, wastewater, drinking water, or via animal disease vectors (although some animals can contract the virus from humans). It very rarely transmits from mother to baby during pregnancy.

 

Social distancing and the wearing of cloth face masks, surgical masks, respirators, or other face coverings are controls for droplet transmission. Transmission may be decreased indoors with well maintained heating and ventilation systems to maintain good air circulation and increase the use of outdoor air.

 

The number of people generally infected by one infected person varies. Coronavirus disease 2019 is more infectious than influenza, but less so than measles. It often spreads in clusters, where infections can be traced back to an index case or geographical location. There is a major role of "super-spreading events", where many people are infected by one person.

 

A person who is infected can transmit the virus to others up to two days before they themselves show symptoms, and even if symptoms never appear. People remain infectious in moderate cases for 7–12 days, and up to two weeks in severe cases. In October 2020, medical scientists reported evidence of reinfection in one person.

 

VIROLOGY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature.

 

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.

 

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have an animal (zoonotic) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The structure of the M protein resembles the sugar transporter SemiSWEET.

 

The many thousands of SARS-CoV-2 variants are grouped into clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR).

 

Several notable variants of SARS-CoV-2 emerged in late 2020. Cluster 5 emerged among minks and mink farmers in Denmark. After strict quarantines and a mink euthanasia campaign, it is believed to have been eradicated. The Variant of Concern 202012/01 (VOC 202012/01) is believed to have emerged in the United Kingdom in September. The 501Y.V2 Variant, which has the same N501Y mutation, arose independently in South Africa.

 

SARS-CoV-2 VARIANTS

Three known variants of SARS-CoV-2 are currently spreading among global populations as of January 2021 including the UK Variant (referred to as B.1.1.7) first found in London and Kent, a variant discovered in South Africa (referred to as 1.351), and a variant discovered in Brazil (referred to as P.1).

 

Using Whole Genome Sequencing, epidemiology and modelling suggest the new UK variant ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020) transmits more easily than other strains.

 

PATHOPHYSIOLOGY

COVID-19 can affect the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective. As the alveolar disease progresses, respiratory failure might develop and death may follow.

 

Whether SARS-CoV-2 is able to invade the nervous system remains unknown. The virus is not detected in the CNS of the majority of COVID-19 people with neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID-19, but these results need to be confirmed. SARS-CoV-2 could cause respiratory failure through affecting the brain stem as other coronaviruses have been found to invade the CNS. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood-brain barrier to gain access to the CNS, possibly within an infected white blood cell.

 

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

 

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism have been found people transferred to Intensive care unit (ICU) with COVID-19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in people infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia. Furthermore, microvascular blood vessel damage has been reported in a small number of tissue samples of the brains – without detected SARS-CoV-2 – and the olfactory bulbs from those who have died from COVID-19.

 

Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of hospitalized patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

 

Autopsies of people who died of COVID-19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.

 

IMMUNOPATHOLOGY

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID-19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.

 

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

 

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID-19 . Lymphocytic infiltrates have also been reported at autopsy.

 

VIRAL AND HOST FACTORS

VIRUS PROTEINS

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus host range and cellular tropism via the receptor binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID-19 vaccines.

 

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response.

 

HOST FACTORS

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-COV2 virus targets causing COVID-19. Theoretically the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID-19, though animal data suggest some potential protective effect of ARB. However no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.

 

The virus' effect on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome.

 

HOST CYTOKINE RESPONSE

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm. Levels of interleukin 1B, interferon-gamma, interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID-19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID-19 disease.

 

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID-19, it is related to worse prognosis and increased fatality. The storm causes the acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis, acute kidney injury, and vasculitis. The production of IL-1, IL-2, IL-6, TNF-alpha, and interferon-gamma, all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system, the microglia, neurons, and astrocytes, are also be involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.

 

DIAGNOSIS

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.

 

VIRAL TESTING

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests, which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited." The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease.

 

A number of laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK.

 

The University of Oxford's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" On 7 September, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results."

 

IMAGING

Chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.

 

Many groups have created COVID-19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID-19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive.

Coding

In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.

 

PATHOLOGY

The main pathological findings at autopsy are:

 

Macroscopy: pericarditis, lung consolidation and pulmonary oedema

Lung findings:

minor serous exudation, minor fibrin exudation

pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation

diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

plasmocytosis in BAL

Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

Liver: microvesicular steatosis

 

PREVENTION

Preventive measures to reduce the chances of infection include staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.

 

Those diagnosed with COVID-19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.

 

The first COVID-19 vaccine was granted regulatory approval on 2 December by the UK medicines regulator MHRA. It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID-19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID-19 is trying to decrease and delay the epidemic peak, known as "flattening the curve". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.

 

VACCINE

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus causing coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which enabled accelerated development of various vaccine technologies during early 2020. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19.

 

In Phase III trials, several COVID‑19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of March 2021, 12 vaccines were authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, and CoviVac), four viral vector vaccines (Sputnik V, the Oxford–AstraZeneca vaccine, Convidicea, and the Johnson & Johnson vaccine), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer). In total, as of March 2021, 308 vaccine candidates were in various stages of development, with 73 in clinical research, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development.

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. As of 17 March 2021, 400.22 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses, and Sputnik V, Sinopharm, Sinovac, and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. 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.

 

SOCIAL DISTANCING

Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. Many governments are now mandating or recommending social distancing in regions affected by the outbreak.

 

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.

 

SELF-ISOLATION

Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.

Face masks and respiratory hygiene

 

The WHO and the US CDC recommend individuals wear non-medical face coverings in public settings where there is an increased risk of transmission and where social distancing measures are difficult to maintain. This recommendation is meant to reduce the spread of the disease by asymptomatic and pre-symptomatic individuals and is complementary to established preventive measures such as social distancing. Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing. A face covering without vents or holes will also filter out particles containing the virus from inhaled and exhaled air, reducing the chances of infection. But, if the mask include an exhalation valve, a wearer that is infected (maybe without having noticed that, and asymptomatic) would transmit the virus outwards through it, despite any certification they can have. So the masks with exhalation valve are not for the infected wearers, and are not reliable to stop the pandemic in a large scale. Many countries and local jurisdictions encourage or mandate the use of face masks or cloth face coverings by members of the public to limit the spread of the virus.

 

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease. When not wearing a mask, the CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. Healthcare professionals interacting directly with people who have COVID-19 are advised to use respirators at least as protective as NIOSH-certified N95 or equivalent, in addition to other personal protective equipment.

 

HAND-WASHING AND HYGIENE

Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. The CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

 

SURFACE CLEANING

After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body cause infection. Current evidence indicates that contact with infected surfaces is not the main driver of Covid-19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticized as hygiene theater, giving a false sense of security against something primarily spread through the air.

 

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight. Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%).

 

On many surfaces, including as glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. As a general rule of thumb, the virus dies faster on porous surfaces than on non-porous surfaces.

However, this rule is not absolute, and of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces.

 

Surfaces may be decontaminated with 62–71 percent ethanol, 50–100 percent isopropanol, 0.1 percent sodium hypochlorite, 0.5 percent hydrogen peroxide, and 0.2–7.5 percent povidone-iodine. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used. The CDC recommends that if a COVID-19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons should be disinfected. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inocuylum volumes) can be seen in the supplementary material of.

 

VENTILATION AND AIR FILTRATION

The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.

 

HEALTHY DIET AND LIFESTYLE

The Harvard T.H. Chan School of Public Health recommends a healthy diet, being physically active, managing psychological stress, and getting enough sleep.

 

While there is no evidence that vitamin D is an effective treatment for COVID-19, there is limited evidence that vitamin D deficiency increases the risk of severe COVID-19 symptoms. This has led to recommendations for individuals with vitamin D deficiency to take vitamin D supplements as a way of mitigating the risk of COVID-19 and other health issues associated with a possible increase in deficiency due to social distancing.

 

TREATMENT

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. Thus, the cornerstone of management of COVID-19 is supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

 

Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.

 

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.

Several experimental treatments are being actively studied in clinical trials. Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful. Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment. Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy.

 

PROGNOSIS

The severity of COVID-19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalization. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID-19 and with a transfer to ICU.

 

Some early studies suggest 10% to 20% of people with COVID-19 will experience symptoms lasting longer than a month.[191][192] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020 WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID-19 symptoms that fluctuate over time as "really concerning." They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros has concluded that therefore herd immunity is "morally unconscionable and unfeasible".

 

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within 2 months of discharge. The average to readmit was 8 days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease.

 

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers, air pollution is similarly associated with risk factors, and pre-existing heart and lung diseases and also obesity contributes to an increased health risk of COVID-19.

 

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research that looked into the COVID-19 infections in hospitalized kidney transplant recipients found a mortality rate of 11%.

See also: Impact of the COVID-19 pandemic on children

 

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years. They are likely to have milder symptoms and a lower chance of severe disease than adults. A European multinational study of hospitalized children published in The Lancet on 25 June 2020 found that about 8% of children admitted to a hospital needed intensive care. Four of those 582 children (0.7%) died, but the actual mortality rate could be "substantially lower" since milder cases that did not seek medical help were not included in the study.

 

Genetics also plays an important role in the ability to fight off the disease. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID-19. Genetic screening is able to detect interferon effector genes.

 

Pregnant women may be at higher risk of severe COVID-19 infection based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.

 

COMPLICATIONS

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death. Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots. Approximately 20–30% of people who present with COVID-19 have elevated liver enzymes, reflecting liver injury.

 

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions). Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID-19 and have an altered mental status.

 

LONGER-TERM EFFECTS

Some early studies suggest that that 10 to 20% of people with COVID-19 will experience symptoms lasting longer than a month. A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath. About 5-10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.

 

By a variety of mechanisms, the lungs are the organs most affected in COVID-19.[228] The majority of CT scans performed show lung abnormalities in people tested after 28 days of illness.

 

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long lasting effects, including pulmonary fibrosis. Overall, approximately one third of those investigated after 4 weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in people who are asymptomatic, but with the suggestion of continuing improvement with the passing of more time.

 

IMMUNITY

The immune response by humans to CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralizing antibodies in blood strongly correlates with protection from infection, but the level of neutralizing antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralizing antibody two months after infection. In another study, the level of neutralizing antibody fell 4-fold 1 to 4 months after the onset of symptoms. However, the lack of antibody in the blood does not mean antibody will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least 6 months after appearance of symptoms. Nevertheless, 15 cases of reinfection with SARS-CoV-2 have been reported using stringent CDC criteria requiring identification of a different variant from the second infection. There are likely to be many more people who have been reinfected with the virus. Herd immunity will not eliminate the virus if reinfection is common. Some other coronaviruses circulating in people are capable of reinfection after roughly a year. Nonetheless, on 3 March 2021, scientists reported that a much more contagious Covid-19 variant, Lineage P.1, first detected in Japan, and subsequently found in Brazil, as well as in several places in the United States, may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.

 

MORTALITY

Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly.

 

The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 2.2% (2,685,770/121,585,388) as of 18 March 2021. The number varies by region. The CFR may not reflect the true severity of the disease, because some infected individuals remain asymptomatic or experience only mild symptoms, and hence such infections may not be included in official case reports. Moreover, the CFR may vary markedly over time and across locations due to the availability of live virus tests.

 

INFECTION FATALITY RATE

A key metric in gauging the severity of COVID-19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk. This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR, the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases.

 

CURRENT ESTIMATES

A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO.

 

EARLIER ESTIMATES OF IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.[ On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID-19 (0.3% of the population).Antibody testing in New York City suggested an IFR of ~0.9%,[258] and ~1.4%. In Bergamo province, 0.6% of the population has died. In September 2020 the U.S. Center for Disease Control & Prevention reported preliminary estimates of age-specific IFRs for public health planning purposes.

 

SEX DIFFERENCES

Early reviews of epidemiologic data showed gendered impact of the pandemic and a higher mortality rate in men in China and Italy. The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected people were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.

 

ETHNIC DIFFERENCES

In the US, a greater proportion of deaths due to COVID-19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the U.K., a greater proportion of deaths due to COVID-19 have occurred in those of a Black, Asian, and other ethnic minority background. More severe impacts upon victims including the relative incidence of the necessity of hospitalization requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet. This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe.

 

COMORBIDITIES

Most of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease. According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), Ischemic Heart Disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths).

 

Most critical respiratory comorbidities according to the CDC, are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis. Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms. COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.

 

In August 2020 the CDC issued a caution that tuberculosis infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID-19 couldn't rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB related deaths by 2025.

 

NAME

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu, Middle East Respiratory Syndrome, and Zika virus. In January 2020, the WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species, or groups of people in disease and virus names in part to prevent social stigma. The official names COVID-19 and SARS-CoV-2 were issued by the WHO on 11 February 2020. Tedros Adhanom explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.

 

HISTORY

The virus is thought to be natural and of an animal origin, through spillover infection. There are several theories about where the first case (the so-called patient zero) originated. Phylogenetics estimates that SARS-CoV-2 arose in October or November 2019. Evidence suggests that it descends from a coronavirus that infects wild bats, and spread to humans through an intermediary wildlife host.

 

The first known human infections were in Wuhan, Hubei, China. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as 1 December 2019.Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals. In May 2020 George Gao, the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event, but that it was not the site of the initial outbreak.[ Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.

 

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of coronavirus cases in Hubei gradually increased, reaching 60 by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS, causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.

 

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases—enough to trigger an investigation.

 

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen. Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared the coronavirus a Public Health Emergency of International Concern. By this time, the outbreak spread by a factor of 100 to 200 times.

 

Italy had its first confirmed cases on 31 January 2020, two tourists from China. As of 13 March 2020 the WHO considered Europe the active centre of the pandemic. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020.

 

After 55 days without a locally transmitted case, Beijing reported a new COVID-19 case on 11 June 2020 which was followed by two more cases on 12 June. By 15 June there were 79 cases officially confirmed, most of them were people that went to Xinfadi Wholesale Market.

 

RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID-19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December.

 

MISINFORMATION

After the initial outbreak of COVID-19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online.

 

In September 2020, the U.S. CDC published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.

 

OTHER ANIMALS

Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis.

 

Some pets, especially cats and ferrets, can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviors which increase the risk of transmission include kissing, licking, and petting the animal.

 

The virus does not appear to be able to infect pigs, ducks, or chickens at all.[ Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.

 

Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID-19 virus.

 

Minks, which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms. Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations. A vaccine for mink and other animals is being researched.

 

RESEARCH

International research on vaccines and medicines in COVID-19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.

 

As of December 2020, hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica. As of November 2020, more than 200 possible treatments had been studied in humans so far.

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on epidemiological models, estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID-19 including computational fluid dynamics models to study the flow physics of COVID-19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID-19 on organizations worldwide.

 

TREATMENT-RELATED RESEARCH

Repurposed antiviral drugs make up most of the research into COVID-19 treatments. Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.

 

In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs, lopinavir/ritonavir; and interferon-beta. More than 300 active clinical trials were underway as of April 2020.

 

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020, France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID-19 treatment.

 

In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID-19 who do not require supplemental oxygen.

 

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID-19 patients.

 

WIKIPEDIA

It really is a wonder drug for my Crohn's Disease, however the side effects are truly horrific: en.wikipedia.org/wiki/Prednisone#Side-effects

 

Strobist Info: SB-800 fired via Nikon CLS through translucent Umbrellea directly in front of subject.

 

Blog Entry w/ this Photo: www.justinrosenberg.com/2009/01/08/stuck-at-home-sick/

Neuroscientists point out that such kissing employs the lips and tongue; highly sensitive areas with lots of afferent neurons sending signals to the brain to release endorphins. These make us go all gooey. Kissing helps prevent hormone-glucocorticoids from forming which can result in stress and high cholesterol. Instead, kissing creates an adrenaline rush which combats hydrocortisone, a stress hormone. Kissing burns up calories in exercising dozens of little face muscles, increasing blood circulation which helps smooth out wrinkles.

Prezzo: 70,00€

 

Blend esclusivo di attivi con una rivoluzionaria doppia azione: ripristinano l’omeostasi della pelle proteggendola dai segnali di stress interni e ripristinando il suo naturale ritmo circadiano.

Olio per il viso caratterizzato da una sinergia pregiata di oli fermentati: una nuova categoria di oli vegetali prodotti attraverso l’esclusiva tecnologia di fermentazione dell’olio che comporta una concentrazione di acidi grassi liberi più elevati ed un miglioramento dell’assorbimento cutaneo.

Delightful oil è un potente cronocosmetico che ha due caratteristiche fondamentali:

1. Inibisce l’attività glucocorticoide

Lo stress può significativamente modificare i livelli di cortisolo detto anche “ormone dello stress” che regolati dal nostro orologio interno, manifestano un picco al mattino presto per poi scemare verso mezzogiorno. Quando i livelli vengono sfalsati i glucocorticoidi, come il cortisolo, possono influenzare l’omeostasi della pelle e portare ad un invecchiamento prematuro ed una pelle spenta.

Delightful oil, grazie alla presenza di un attivo di ultima generazione, inibendo l’attività dei due neurotrasmettitori, quali cortisolo e adrenalina, è in grado di ridurre il danno al livello del DNA nei cheratinociti, e portare ad una pelle del viso più rilassata, eludendo i prematuri segnali di invecchiamento. Anche la luminosità del viso è un aspetto che può dipendere dal cortisolo, che alterando la barriera della pelle, può portare a ridurla. Delightful oil, grazie al suo effetto rilassante, è in grado di potenziare la luminosità della viso.

2. E’ formato da oli fermentati

È ben noto che la penetrazione dei composti attivi dipende dalle dimensioni delle molecole. Le proprietà e i componenti delle materie prime vengono modificati durante il processo di fermentazione che è un processo di conversione di composti organici attraverso l’uso di vari microorganismi. Da tale processo si ottengono attivi maggiormente biodisponibili proprio grazie alle loro dimensioni più piccole e questo aiuta una migliore penetrazione nella pelle.

Delightful oil è caratterizzato da una sinergia di differenti oli fermentati (Oliva, Argan, Liquirizia, Albicocca, Mandorla) e dallo Shiunko, un esclusivo blend di oli fermentati prodotti dall’Angelica sinensis e dal Lithospermum erythorihizon, dalle spiccate proprietà antiossidanti.

Un concentrato di vitalità mirato a rafforzare e proteggere il reticolo cutaneo rassodando e ridefinendo i contorni del viso, per una pelle tonica ed elastica.

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic.

 

Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. Of those people who develop noticeable symptoms, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging), and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). Older people are more likely to have severe symptoms. At least a third of the people who are infected with the virus remain asymptomatic and do not develop noticeable symptoms at any point in time, but they still can spread the disease.[ Around 20% of those people will remain asymptomatic throughout infection, and the rest will develop symptoms later on, becoming pre-symptomatic rather than asymptomatic and therefore having a higher risk of transmitting the virus to others. Some people continue to experience a range of effects—known as long COVID—for months after recovery, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

The virus that causes COVID-19 spreads mainly when an infected person is in close contact[a] with another person. Small droplets and aerosols containing the virus can spread from an infected person's nose and mouth as they breathe, cough, sneeze, sing, or speak. Other people are infected if the virus gets into their mouth, nose or eyes. The virus may also spread via contaminated surfaces, although this is not thought to be the main route of transmission. The exact route of transmission is rarely proven conclusively, but infection mainly happens when people are near each other for long enough. People who are infected can transmit the virus to another person up to two days before they themselves show symptoms, as can people who do not experience symptoms. People remain infectious for up to ten days after the onset of symptoms in moderate cases and up to 20 days in severe cases. Several testing methods have been developed to diagnose the disease. The standard diagnostic method is by detection of the virus' nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

 

Preventive measures include physical or social distancing, quarantining, ventilation of indoor spaces, covering coughs and sneezes, hand washing, and keeping unwashed hands away from the face. The use of face masks or coverings has been recommended in public settings to minimise the risk of transmissions. Several vaccines have been developed and several countries have initiated mass vaccination campaigns.

 

Although work is underway to develop drugs that inhibit the virus, the primary treatment is currently symptomatic. Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.

 

SIGNS AND SYSTOMS

Symptoms of COVID-19 are variable, ranging from mild symptoms to severe illness. Common symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, and breathing difficulties. People with the same infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, and throat disorders, loss of taste combined with loss of smell is associated with COVID-19.

 

Most people (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) and 5% of patients suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can spread the disease. Other infected people will develop symptoms later, called "pre-symptomatic", or have very mild symptoms and can also spread the virus.

 

As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.

Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects for months after recovery—named long COVID—and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

CAUSE

TRANSMISSION

Coronavirus disease 2019 (COVID-19) spreads from person to person mainly through the respiratory route after an infected person coughs, sneezes, sings, talks or breathes. A new infection occurs when virus-containing particles exhaled by an infected person, either respiratory droplets or aerosols, get into the mouth, nose, or eyes of other people who are in close contact with the infected person. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection.

 

The closer people interact, and the longer they interact, the more likely they are to transmit COVID-19. Closer distances can involve larger droplets (which fall to the ground) and aerosols, whereas longer distances only involve aerosols. Larger droplets can also turn into aerosols (known as droplet nuclei) through evaporation. The relative importance of the larger droplets and the aerosols is not clear as of November 2020; however, the virus is not known to spread between rooms over long distances such as through air ducts. Airborne transmission is able to particularly occur indoors, in high risk locations such as restaurants, choirs, gyms, nightclubs, offices, and religious venues, often when they are crowded or less ventilated. It also occurs in healthcare settings, often when aerosol-generating medical procedures are performed on COVID-19 patients.

 

Although it is considered possible there is no direct evidence of the virus being transmitted by skin to skin contact. A person could get COVID-19 indirectly by touching a contaminated surface or object before touching their own mouth, nose, or eyes, though this is not thought to be the main way the virus spreads. The virus is not known to spread through feces, urine, breast milk, food, wastewater, drinking water, or via animal disease vectors (although some animals can contract the virus from humans). It very rarely transmits from mother to baby during pregnancy.

 

Social distancing and the wearing of cloth face masks, surgical masks, respirators, or other face coverings are controls for droplet transmission. Transmission may be decreased indoors with well maintained heating and ventilation systems to maintain good air circulation and increase the use of outdoor air.

 

The number of people generally infected by one infected person varies. Coronavirus disease 2019 is more infectious than influenza, but less so than measles. It often spreads in clusters, where infections can be traced back to an index case or geographical location. There is a major role of "super-spreading events", where many people are infected by one person.

 

A person who is infected can transmit the virus to others up to two days before they themselves show symptoms, and even if symptoms never appear. People remain infectious in moderate cases for 7–12 days, and up to two weeks in severe cases. In October 2020, medical scientists reported evidence of reinfection in one person.

 

VIROLOGY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature.

 

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.

 

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have an animal (zoonotic) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The structure of the M protein resembles the sugar transporter SemiSWEET.

 

The many thousands of SARS-CoV-2 variants are grouped into clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR).

 

Several notable variants of SARS-CoV-2 emerged in late 2020. Cluster 5 emerged among minks and mink farmers in Denmark. After strict quarantines and a mink euthanasia campaign, it is believed to have been eradicated. The Variant of Concern 202012/01 (VOC 202012/01) is believed to have emerged in the United Kingdom in September. The 501Y.V2 Variant, which has the same N501Y mutation, arose independently in South Africa.

 

SARS-CoV-2 VARIANTS

Three known variants of SARS-CoV-2 are currently spreading among global populations as of January 2021 including the UK Variant (referred to as B.1.1.7) first found in London and Kent, a variant discovered in South Africa (referred to as 1.351), and a variant discovered in Brazil (referred to as P.1).

 

Using Whole Genome Sequencing, epidemiology and modelling suggest the new UK variant ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020) transmits more easily than other strains.

 

PATHOPHYSIOLOGY

COVID-19 can affect the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective. As the alveolar disease progresses, respiratory failure might develop and death may follow.

 

Whether SARS-CoV-2 is able to invade the nervous system remains unknown. The virus is not detected in the CNS of the majority of COVID-19 people with neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID-19, but these results need to be confirmed. SARS-CoV-2 could cause respiratory failure through affecting the brain stem as other coronaviruses have been found to invade the CNS. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood-brain barrier to gain access to the CNS, possibly within an infected white blood cell.

 

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

 

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism have been found people transferred to Intensive care unit (ICU) with COVID-19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in people infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia. Furthermore, microvascular blood vessel damage has been reported in a small number of tissue samples of the brains – without detected SARS-CoV-2 – and the olfactory bulbs from those who have died from COVID-19.

 

Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of hospitalized patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

 

Autopsies of people who died of COVID-19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.

 

IMMUNOPATHOLOGY

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID-19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.

 

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

 

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID-19 . Lymphocytic infiltrates have also been reported at autopsy.

 

VIRAL AND HOST FACTORS

VIRUS PROTEINS

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus host range and cellular tropism via the receptor binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID-19 vaccines.

 

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response.

 

HOST FACTORS

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-COV2 virus targets causing COVID-19. Theoretically the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID-19, though animal data suggest some potential protective effect of ARB. However no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.

 

The virus' effect on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome.

 

HOST CYTOKINE RESPONSE

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm. Levels of interleukin 1B, interferon-gamma, interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID-19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID-19 disease.

 

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID-19, it is related to worse prognosis and increased fatality. The storm causes the acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis, acute kidney injury, and vasculitis. The production of IL-1, IL-2, IL-6, TNF-alpha, and interferon-gamma, all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system, the microglia, neurons, and astrocytes, are also be involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.

 

DIAGNOSIS

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.

 

VIRAL TESTING

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests, which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited." The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease.

 

A number of laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK.

 

The University of Oxford's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" On 7 September, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results."

 

IMAGING

Chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.

 

Many groups have created COVID-19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID-19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive.

Coding

In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.

 

PATHOLOGY

The main pathological findings at autopsy are:

 

Macroscopy: pericarditis, lung consolidation and pulmonary oedema

Lung findings:

minor serous exudation, minor fibrin exudation

pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation

diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

plasmocytosis in BAL

Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

Liver: microvesicular steatosis

 

PREVENTION

Preventive measures to reduce the chances of infection include staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.

 

Those diagnosed with COVID-19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.

 

The first COVID-19 vaccine was granted regulatory approval on 2 December by the UK medicines regulator MHRA. It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID-19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID-19 is trying to decrease and delay the epidemic peak, known as "flattening the curve". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.

 

VACCINE

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus causing coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which enabled accelerated development of various vaccine technologies during early 2020. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19.

 

In Phase III trials, several COVID‑19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of March 2021, 12 vaccines were authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, and CoviVac), four viral vector vaccines (Sputnik V, the Oxford–AstraZeneca vaccine, Convidicea, and the Johnson & Johnson vaccine), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer). In total, as of March 2021, 308 vaccine candidates were in various stages of development, with 73 in clinical research, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development.

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. As of 17 March 2021, 400.22 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses, and Sputnik V, Sinopharm, Sinovac, and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. 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.

 

SOCIAL DISTANCING

Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. Many governments are now mandating or recommending social distancing in regions affected by the outbreak.

 

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.

 

SELF-ISOLATION

Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.

Face masks and respiratory hygiene

 

The WHO and the US CDC recommend individuals wear non-medical face coverings in public settings where there is an increased risk of transmission and where social distancing measures are difficult to maintain. This recommendation is meant to reduce the spread of the disease by asymptomatic and pre-symptomatic individuals and is complementary to established preventive measures such as social distancing. Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing. A face covering without vents or holes will also filter out particles containing the virus from inhaled and exhaled air, reducing the chances of infection. But, if the mask include an exhalation valve, a wearer that is infected (maybe without having noticed that, and asymptomatic) would transmit the virus outwards through it, despite any certification they can have. So the masks with exhalation valve are not for the infected wearers, and are not reliable to stop the pandemic in a large scale. Many countries and local jurisdictions encourage or mandate the use of face masks or cloth face coverings by members of the public to limit the spread of the virus.

 

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease. When not wearing a mask, the CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. Healthcare professionals interacting directly with people who have COVID-19 are advised to use respirators at least as protective as NIOSH-certified N95 or equivalent, in addition to other personal protective equipment.

 

HAND-WASHING AND HYGIENE

Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. The CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

 

SURFACE CLEANING

After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body cause infection. Current evidence indicates that contact with infected surfaces is not the main driver of Covid-19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticized as hygiene theater, giving a false sense of security against something primarily spread through the air.

 

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight. Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%).

 

On many surfaces, including as glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. As a general rule of thumb, the virus dies faster on porous surfaces than on non-porous surfaces.

However, this rule is not absolute, and of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces.

 

Surfaces may be decontaminated with 62–71 percent ethanol, 50–100 percent isopropanol, 0.1 percent sodium hypochlorite, 0.5 percent hydrogen peroxide, and 0.2–7.5 percent povidone-iodine. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used. The CDC recommends that if a COVID-19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons should be disinfected. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inocuylum volumes) can be seen in the supplementary material of.

 

VENTILATION AND AIR FILTRATION

The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.

 

HEALTHY DIET AND LIFESTYLE

The Harvard T.H. Chan School of Public Health recommends a healthy diet, being physically active, managing psychological stress, and getting enough sleep.

 

While there is no evidence that vitamin D is an effective treatment for COVID-19, there is limited evidence that vitamin D deficiency increases the risk of severe COVID-19 symptoms. This has led to recommendations for individuals with vitamin D deficiency to take vitamin D supplements as a way of mitigating the risk of COVID-19 and other health issues associated with a possible increase in deficiency due to social distancing.

 

TREATMENT

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. Thus, the cornerstone of management of COVID-19 is supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

 

Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.

 

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.

Several experimental treatments are being actively studied in clinical trials. Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful. Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment. Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy.

 

PROGNOSIS

The severity of COVID-19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalization. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID-19 and with a transfer to ICU.

 

Some early studies suggest 10% to 20% of people with COVID-19 will experience symptoms lasting longer than a month.[191][192] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020 WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID-19 symptoms that fluctuate over time as "really concerning." They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros has concluded that therefore herd immunity is "morally unconscionable and unfeasible".

 

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within 2 months of discharge. The average to readmit was 8 days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease.

 

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers, air pollution is similarly associated with risk factors, and pre-existing heart and lung diseases and also obesity contributes to an increased health risk of COVID-19.

 

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research that looked into the COVID-19 infections in hospitalized kidney transplant recipients found a mortality rate of 11%.

See also: Impact of the COVID-19 pandemic on children

 

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years. They are likely to have milder symptoms and a lower chance of severe disease than adults. A European multinational study of hospitalized children published in The Lancet on 25 June 2020 found that about 8% of children admitted to a hospital needed intensive care. Four of those 582 children (0.7%) died, but the actual mortality rate could be "substantially lower" since milder cases that did not seek medical help were not included in the study.

 

Genetics also plays an important role in the ability to fight off the disease. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID-19. Genetic screening is able to detect interferon effector genes.

 

Pregnant women may be at higher risk of severe COVID-19 infection based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.

 

COMPLICATIONS

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death. Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots. Approximately 20–30% of people who present with COVID-19 have elevated liver enzymes, reflecting liver injury.

 

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions). Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID-19 and have an altered mental status.

 

LONGER-TERM EFFECTS

Some early studies suggest that that 10 to 20% of people with COVID-19 will experience symptoms lasting longer than a month. A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath. About 5-10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.

 

By a variety of mechanisms, the lungs are the organs most affected in COVID-19.[228] The majority of CT scans performed show lung abnormalities in people tested after 28 days of illness.

 

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long lasting effects, including pulmonary fibrosis. Overall, approximately one third of those investigated after 4 weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in people who are asymptomatic, but with the suggestion of continuing improvement with the passing of more time.

 

IMMUNITY

The immune response by humans to CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralizing antibodies in blood strongly correlates with protection from infection, but the level of neutralizing antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralizing antibody two months after infection. In another study, the level of neutralizing antibody fell 4-fold 1 to 4 months after the onset of symptoms. However, the lack of antibody in the blood does not mean antibody will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least 6 months after appearance of symptoms. Nevertheless, 15 cases of reinfection with SARS-CoV-2 have been reported using stringent CDC criteria requiring identification of a different variant from the second infection. There are likely to be many more people who have been reinfected with the virus. Herd immunity will not eliminate the virus if reinfection is common. Some other coronaviruses circulating in people are capable of reinfection after roughly a year. Nonetheless, on 3 March 2021, scientists reported that a much more contagious Covid-19 variant, Lineage P.1, first detected in Japan, and subsequently found in Brazil, as well as in several places in the United States, may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.

 

MORTALITY

Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly.

 

The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 2.2% (2,685,770/121,585,388) as of 18 March 2021. The number varies by region. The CFR may not reflect the true severity of the disease, because some infected individuals remain asymptomatic or experience only mild symptoms, and hence such infections may not be included in official case reports. Moreover, the CFR may vary markedly over time and across locations due to the availability of live virus tests.

 

INFECTION FATALITY RATE

A key metric in gauging the severity of COVID-19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk. This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR, the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases.

 

CURRENT ESTIMATES

A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO.

 

EARLIER ESTIMATES OF IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.[ On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID-19 (0.3% of the population).Antibody testing in New York City suggested an IFR of ~0.9%,[258] and ~1.4%. In Bergamo province, 0.6% of the population has died. In September 2020 the U.S. Center for Disease Control & Prevention reported preliminary estimates of age-specific IFRs for public health planning purposes.

 

SEX DIFFERENCES

Early reviews of epidemiologic data showed gendered impact of the pandemic and a higher mortality rate in men in China and Italy. The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected people were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.

 

ETHNIC DIFFERENCES

In the US, a greater proportion of deaths due to COVID-19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the U.K., a greater proportion of deaths due to COVID-19 have occurred in those of a Black, Asian, and other ethnic minority background. More severe impacts upon victims including the relative incidence of the necessity of hospitalization requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet. This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe.

 

COMORBIDITIES

Most of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease. According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), Ischemic Heart Disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths).

 

Most critical respiratory comorbidities according to the CDC, are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis. Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms. COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.

 

In August 2020 the CDC issued a caution that tuberculosis infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID-19 couldn't rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB related deaths by 2025.

 

NAME

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu, Middle East Respiratory Syndrome, and Zika virus. In January 2020, the WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species, or groups of people in disease and virus names in part to prevent social stigma. The official names COVID-19 and SARS-CoV-2 were issued by the WHO on 11 February 2020. Tedros Adhanom explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.

 

HISTORY

The virus is thought to be natural and of an animal origin, through spillover infection. There are several theories about where the first case (the so-called patient zero) originated. Phylogenetics estimates that SARS-CoV-2 arose in October or November 2019. Evidence suggests that it descends from a coronavirus that infects wild bats, and spread to humans through an intermediary wildlife host.

 

The first known human infections were in Wuhan, Hubei, China. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as 1 December 2019.Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals. In May 2020 George Gao, the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event, but that it was not the site of the initial outbreak.[ Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.

 

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of coronavirus cases in Hubei gradually increased, reaching 60 by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS, causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.

 

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases—enough to trigger an investigation.

 

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen. Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared the coronavirus a Public Health Emergency of International Concern. By this time, the outbreak spread by a factor of 100 to 200 times.

 

Italy had its first confirmed cases on 31 January 2020, two tourists from China. As of 13 March 2020 the WHO considered Europe the active centre of the pandemic. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020.

 

After 55 days without a locally transmitted case, Beijing reported a new COVID-19 case on 11 June 2020 which was followed by two more cases on 12 June. By 15 June there were 79 cases officially confirmed, most of them were people that went to Xinfadi Wholesale Market.

 

RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID-19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December.

 

MISINFORMATION

After the initial outbreak of COVID-19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online.

 

In September 2020, the U.S. CDC published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.

 

OTHER ANIMALS

Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis.

 

Some pets, especially cats and ferrets, can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviors which increase the risk of transmission include kissing, licking, and petting the animal.

 

The virus does not appear to be able to infect pigs, ducks, or chickens at all.[ Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.

 

Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID-19 virus.

 

Minks, which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms. Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations. A vaccine for mink and other animals is being researched.

 

RESEARCH

International research on vaccines and medicines in COVID-19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.

 

As of December 2020, hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica. As of November 2020, more than 200 possible treatments had been studied in humans so far.

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on epidemiological models, estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID-19 including computational fluid dynamics models to study the flow physics of COVID-19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID-19 on organizations worldwide.

 

TREATMENT-RELATED RESEARCH

Repurposed antiviral drugs make up most of the research into COVID-19 treatments. Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.

 

In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs, lopinavir/ritonavir; and interferon-beta. More than 300 active clinical trials were underway as of April 2020.

 

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020, France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID-19 treatment.

 

In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID-19 who do not require supplemental oxygen.

 

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID-19 patients.

 

WIKIPEDIA

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, leading to an ongoing pandemic.

 

Symptoms of COVID-19 are variable, but often include fever, cough, fatigue, breathing difficulties, and loss of smell and taste. Symptoms begin one to fourteen days after exposure to the virus. Of those people who develop noticeable symptoms, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging), and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). Older people are more likely to have severe symptoms. At least a third of the people who are infected with the virus remain asymptomatic and do not develop noticeable symptoms at any point in time, but they still can spread the disease.[ Around 20% of those people will remain asymptomatic throughout infection, and the rest will develop symptoms later on, becoming pre-symptomatic rather than asymptomatic and therefore having a higher risk of transmitting the virus to others. Some people continue to experience a range of effects—known as long COVID—for months after recovery, and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

The virus that causes COVID-19 spreads mainly when an infected person is in close contact[a] with another person. Small droplets and aerosols containing the virus can spread from an infected person's nose and mouth as they breathe, cough, sneeze, sing, or speak. Other people are infected if the virus gets into their mouth, nose or eyes. The virus may also spread via contaminated surfaces, although this is not thought to be the main route of transmission. The exact route of transmission is rarely proven conclusively, but infection mainly happens when people are near each other for long enough. People who are infected can transmit the virus to another person up to two days before they themselves show symptoms, as can people who do not experience symptoms. People remain infectious for up to ten days after the onset of symptoms in moderate cases and up to 20 days in severe cases. Several testing methods have been developed to diagnose the disease. The standard diagnostic method is by detection of the virus' nucleic acid by real-time reverse transcription polymerase chain reaction (rRT-PCR), transcription-mediated amplification (TMA), or by reverse transcription loop-mediated isothermal amplification (RT-LAMP) from a nasopharyngeal swab.

 

Preventive measures include physical or social distancing, quarantining, ventilation of indoor spaces, covering coughs and sneezes, hand washing, and keeping unwashed hands away from the face. The use of face masks or coverings has been recommended in public settings to minimise the risk of transmissions. Several vaccines have been developed and several countries have initiated mass vaccination campaigns.

 

Although work is underway to develop drugs that inhibit the virus, the primary treatment is currently symptomatic. Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.

 

SIGNS AND SYSTOMS

Symptoms of COVID-19 are variable, ranging from mild symptoms to severe illness. Common symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle pain, sore throat, fever, diarrhea, and breathing difficulties. People with the same infection may have different symptoms, and their symptoms may change over time. Three common clusters of symptoms have been identified: one respiratory symptom cluster with cough, sputum, shortness of breath, and fever; a musculoskeletal symptom cluster with muscle and joint pain, headache, and fatigue; a cluster of digestive symptoms with abdominal pain, vomiting, and diarrhea. In people without prior ear, nose, and throat disorders, loss of taste combined with loss of smell is associated with COVID-19.

 

Most people (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia, or more than 50% lung involvement on imaging) and 5% of patients suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction). At least a third of the people who are infected with the virus do not develop noticeable symptoms at any point in time. These asymptomatic carriers tend not to get tested and can spread the disease. Other infected people will develop symptoms later, called "pre-symptomatic", or have very mild symptoms and can also spread the virus.

 

As is common with infections, there is a delay between the moment a person first becomes infected and the appearance of the first symptoms. The median delay for COVID-19 is four to five days. Most symptomatic people experience symptoms within two to seven days after exposure, and almost all will experience at least one symptom within 12 days.

Most people recover from the acute phase of the disease. However, some people continue to experience a range of effects for months after recovery—named long COVID—and damage to organs has been observed. Multi-year studies are underway to further investigate the long-term effects of the disease.

 

CAUSE

TRANSMISSION

Coronavirus disease 2019 (COVID-19) spreads from person to person mainly through the respiratory route after an infected person coughs, sneezes, sings, talks or breathes. A new infection occurs when virus-containing particles exhaled by an infected person, either respiratory droplets or aerosols, get into the mouth, nose, or eyes of other people who are in close contact with the infected person. During human-to-human transmission, an average 1000 infectious SARS-CoV-2 virions are thought to initiate a new infection.

 

The closer people interact, and the longer they interact, the more likely they are to transmit COVID-19. Closer distances can involve larger droplets (which fall to the ground) and aerosols, whereas longer distances only involve aerosols. Larger droplets can also turn into aerosols (known as droplet nuclei) through evaporation. The relative importance of the larger droplets and the aerosols is not clear as of November 2020; however, the virus is not known to spread between rooms over long distances such as through air ducts. Airborne transmission is able to particularly occur indoors, in high risk locations such as restaurants, choirs, gyms, nightclubs, offices, and religious venues, often when they are crowded or less ventilated. It also occurs in healthcare settings, often when aerosol-generating medical procedures are performed on COVID-19 patients.

 

Although it is considered possible there is no direct evidence of the virus being transmitted by skin to skin contact. A person could get COVID-19 indirectly by touching a contaminated surface or object before touching their own mouth, nose, or eyes, though this is not thought to be the main way the virus spreads. The virus is not known to spread through feces, urine, breast milk, food, wastewater, drinking water, or via animal disease vectors (although some animals can contract the virus from humans). It very rarely transmits from mother to baby during pregnancy.

 

Social distancing and the wearing of cloth face masks, surgical masks, respirators, or other face coverings are controls for droplet transmission. Transmission may be decreased indoors with well maintained heating and ventilation systems to maintain good air circulation and increase the use of outdoor air.

 

The number of people generally infected by one infected person varies. Coronavirus disease 2019 is more infectious than influenza, but less so than measles. It often spreads in clusters, where infections can be traced back to an index case or geographical location. There is a major role of "super-spreading events", where many people are infected by one person.

 

A person who is infected can transmit the virus to others up to two days before they themselves show symptoms, and even if symptoms never appear. People remain infectious in moderate cases for 7–12 days, and up to two weeks in severe cases. In October 2020, medical scientists reported evidence of reinfection in one person.

 

VIROLOGY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. It was first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan. All structural features of the novel SARS-CoV-2 virus particle occur in related coronaviruses in nature.

 

Outside the human body, the virus is destroyed by household soap, which bursts its protective bubble.

 

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have an animal (zoonotic) origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13). The structural proteins of SARS-CoV-2 include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). The M protein of SARS-CoV-2 is about 98% similar to the M protein of bat SARS-CoV, maintains around 98% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only around 38% with the M protein of MERS-CoV. The structure of the M protein resembles the sugar transporter SemiSWEET.

 

The many thousands of SARS-CoV-2 variants are grouped into clades. Several different clade nomenclatures have been proposed. Nextstrain divides the variants into five clades (19A, 19B, 20A, 20B, and 20C), while GISAID divides them into seven (L, O, V, S, G, GH, and GR).

 

Several notable variants of SARS-CoV-2 emerged in late 2020. Cluster 5 emerged among minks and mink farmers in Denmark. After strict quarantines and a mink euthanasia campaign, it is believed to have been eradicated. The Variant of Concern 202012/01 (VOC 202012/01) is believed to have emerged in the United Kingdom in September. The 501Y.V2 Variant, which has the same N501Y mutation, arose independently in South Africa.

 

SARS-CoV-2 VARIANTS

Three known variants of SARS-CoV-2 are currently spreading among global populations as of January 2021 including the UK Variant (referred to as B.1.1.7) first found in London and Kent, a variant discovered in South Africa (referred to as 1.351), and a variant discovered in Brazil (referred to as P.1).

 

Using Whole Genome Sequencing, epidemiology and modelling suggest the new UK variant ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020) transmits more easily than other strains.

 

PATHOPHYSIOLOGY

COVID-19 can affect the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs). The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a "spike" (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective. As the alveolar disease progresses, respiratory failure might develop and death may follow.

 

Whether SARS-CoV-2 is able to invade the nervous system remains unknown. The virus is not detected in the CNS of the majority of COVID-19 people with neurological issues. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID-19, but these results need to be confirmed. SARS-CoV-2 could cause respiratory failure through affecting the brain stem as other coronaviruses have been found to invade the CNS. While virus has been detected in cerebrospinal fluid of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain. The virus may also enter the bloodstream from the lungs and cross the blood-brain barrier to gain access to the CNS, possibly within an infected white blood cell.

 

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.

 

The virus can cause acute myocardial injury and chronic damage to the cardiovascular system. An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China, and is more frequent in severe disease. Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart. ACE2 receptors are highly expressed in the heart and are involved in heart function. A high incidence of thrombosis and venous thromboembolism have been found people transferred to Intensive care unit (ICU) with COVID-19 infections, and may be related to poor prognosis. Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels caused by blood clots) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in people infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia. Furthermore, microvascular blood vessel damage has been reported in a small number of tissue samples of the brains – without detected SARS-CoV-2 – and the olfactory bulbs from those who have died from COVID-19.

 

Another common cause of death is complications related to the kidneys. Early reports show that up to 30% of hospitalized patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.

 

Autopsies of people who died of COVID-19 have found diffuse alveolar damage, and lymphocyte-containing inflammatory infiltrates within the lung.

 

IMMUNOPATHOLOGY

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID-19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.

 

Additionally, people with COVID-19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.

 

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in people with COVID-19 . Lymphocytic infiltrates have also been reported at autopsy.

 

VIRAL AND HOST FACTORS

VIRUS PROTEINS

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the ACE2 receptors. It includes two subunits: S1 and S2. S1 determines the virus host range and cellular tropism via the receptor binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are heptad repeat regions. Studies have shown that S1 domain induced IgG and IgA antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID-19 vaccines.

 

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope. The N and E protein are accessory proteins that interfere with the host's immune response.

 

HOST FACTORS

Human angiotensin converting enzyme 2 (hACE2) is the host factor that SARS-COV2 virus targets causing COVID-19. Theoretically the usage of angiotensin receptor blockers (ARB) and ACE inhibitors upregulating ACE2 expression might increase morbidity with COVID-19, though animal data suggest some potential protective effect of ARB. However no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.

 

The virus' effect on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a systemic inflammatory response syndrome.

 

HOST CYTOKINE RESPONSE

The severity of the inflammation can be attributed to the severity of what is known as the cytokine storm. Levels of interleukin 1B, interferon-gamma, interferon-inducible protein 10, and monocyte chemoattractant protein 1 were all associated with COVID-19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of morbidity and mortality in COVID-19 disease.

 

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID-19, it is related to worse prognosis and increased fatality. The storm causes the acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, encephalitis, acute kidney injury, and vasculitis. The production of IL-1, IL-2, IL-6, TNF-alpha, and interferon-gamma, all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the central nervous system, the microglia, neurons, and astrocytes, are also be involved in the release of pro-inflammatory cytokines affecting the nervous system, and effects of cytokine storms toward the CNS are not uncommon.

 

DIAGNOSIS

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed using reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid testing of infected secretions. Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection. Detection of a past infection is possible with serological tests, which detect antibodies produced by the body in response to the infection.

 

VIRAL TESTING

The standard methods of testing for presence of SARS-CoV-2 are nucleic acid tests, which detects the presence of viral RNA fragments. As these tests detect RNA but not infectious virus, its "ability to determine duration of infectivity of patients is limited." The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within hours. The WHO has published several testing protocols for the disease.

 

A number of laboratories and companies have developed serological tests, which detect antibodies produced by the body in response to infection. Several have been evaluated by Public Health England and approved for use in the UK.

 

The University of Oxford's CEBM has pointed to mounting evidence that "a good proportion of 'new' mild cases and people re-testing positives after quarantine or discharge from hospital are not infectious, but are simply clearing harmless virus particles which their immune system has efficiently dealt with" and have called for "an international effort to standardize and periodically calibrate testing" On 7 September, the UK government issued "guidance for procedures to be implemented in laboratories to provide assurance of positive SARS-CoV-2 RNA results during periods of low prevalence, when there is a reduction in the predictive value of positive test results."

 

IMAGING

Chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses. Characteristic imaging features on chest radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground-glass opacities without pleural effusions.

 

Many groups have created COVID-19 datasets that include imagery such as the Italian Radiological Society which has compiled an international online database of imaging findings for confirmed cases. Due to overlap with other infections such as adenovirus, imaging without confirmation by rRT-PCR is of limited specificity in identifying COVID-19. A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive.

Coding

In late 2019, the WHO assigned emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.

 

PATHOLOGY

The main pathological findings at autopsy are:

 

Macroscopy: pericarditis, lung consolidation and pulmonary oedema

Lung findings:

minor serous exudation, minor fibrin exudation

pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation

diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.

organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis

plasmocytosis in BAL

Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction

Liver: microvesicular steatosis

 

PREVENTION

Preventive measures to reduce the chances of infection include staying at home, wearing a mask in public, avoiding crowded places, keeping distance from others, ventilating indoor spaces, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.

 

Those diagnosed with COVID-19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider's office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.

 

The first COVID-19 vaccine was granted regulatory approval on 2 December by the UK medicines regulator MHRA. It was evaluated for emergency use authorization (EUA) status by the US FDA, and in several other countries. Initially, the US National Institutes of Health guidelines do not recommend any medication for prevention of COVID-19, before or after exposure to the SARS-CoV-2 virus, outside the setting of a clinical trial. Without a vaccine, other prophylactic measures, or effective treatments, a key part of managing COVID-19 is trying to decrease and delay the epidemic peak, known as "flattening the curve". This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.

 

VACCINE

A COVID‑19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus causing coronavirus disease 2019 (COVID‑19). Prior to the COVID‑19 pandemic, there was an established body of knowledge about the structure and function of coronaviruses causing diseases like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which enabled accelerated development of various vaccine technologies during early 2020. On 10 January 2020, the SARS-CoV-2 genetic sequence data was shared through GISAID, and by 19 March, the global pharmaceutical industry announced a major commitment to address COVID-19.

 

In Phase III trials, several COVID‑19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID‑19 infections. As of March 2021, 12 vaccines were authorized by at least one national regulatory authority for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), four conventional inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, and CoviVac), four viral vector vaccines (Sputnik V, the Oxford–AstraZeneca vaccine, Convidicea, and the Johnson & Johnson vaccine), and two protein subunit vaccines (EpiVacCorona and RBD-Dimer). In total, as of March 2021, 308 vaccine candidates were in various stages of development, with 73 in clinical research, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development.

Many countries have implemented phased distribution plans that prioritize those at highest risk of complications, such as the elderly, and those at high risk of exposure and transmission, such as healthcare workers. As of 17 March 2021, 400.22 million doses of COVID‑19 vaccine have been administered worldwide based on official reports from national health agencies. AstraZeneca-Oxford anticipates producing 3 billion doses in 2021, Pfizer-BioNTech 1.3 billion doses, and Sputnik V, Sinopharm, Sinovac, and Johnson & Johnson 1 billion doses each. Moderna targets producing 600 million doses and Convidicea 500 million doses in 2021. 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.

 

SOCIAL DISTANCING

Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of the disease by minimising close contact between individuals. Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres. Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others. Many governments are now mandating or recommending social distancing in regions affected by the outbreak.

 

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing. In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.

 

SELF-ISOLATION

Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected. Health agencies have issued detailed instructions for proper self-isolation. Many governments have mandated or recommended self-quarantine for entire populations. The strongest self-quarantine instructions have been issued to those in high-risk groups. Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with the widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.

Face masks and respiratory hygiene

 

The WHO and the US CDC recommend individuals wear non-medical face coverings in public settings where there is an increased risk of transmission and where social distancing measures are difficult to maintain. This recommendation is meant to reduce the spread of the disease by asymptomatic and pre-symptomatic individuals and is complementary to established preventive measures such as social distancing. Face coverings limit the volume and travel distance of expiratory droplets dispersed when talking, breathing, and coughing. A face covering without vents or holes will also filter out particles containing the virus from inhaled and exhaled air, reducing the chances of infection. But, if the mask include an exhalation valve, a wearer that is infected (maybe without having noticed that, and asymptomatic) would transmit the virus outwards through it, despite any certification they can have. So the masks with exhalation valve are not for the infected wearers, and are not reliable to stop the pandemic in a large scale. Many countries and local jurisdictions encourage or mandate the use of face masks or cloth face coverings by members of the public to limit the spread of the virus.

 

Masks are also strongly recommended for those who may have been infected and those taking care of someone who may have the disease. When not wearing a mask, the CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available. Proper hand hygiene after any cough or sneeze is encouraged. Healthcare professionals interacting directly with people who have COVID-19 are advised to use respirators at least as protective as NIOSH-certified N95 or equivalent, in addition to other personal protective equipment.

 

HAND-WASHING AND HYGIENE

Thorough hand hygiene after any cough or sneeze is required. The WHO also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose. The CDC recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available. For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is "not an active substance for hand antisepsis". Glycerol is added as a humectant.

 

SURFACE CLEANING

After being expelled from the body, coronaviruses can survive on surfaces for hours to days. If a person touches the dirty surface, they may deposit the virus at the eyes, nose, or mouth where it can enter the body cause infection. Current evidence indicates that contact with infected surfaces is not the main driver of Covid-19, leading to recommendations for optimised disinfection procedures to avoid issues such as the increase of antimicrobial resistance through the use of inappropriate cleaning products and processes. Deep cleaning and other surface sanitation has been criticized as hygiene theater, giving a false sense of security against something primarily spread through the air.

 

The amount of time that the virus can survive depends significantly on the type of surface, the temperature, and the humidity. Coronaviruses die very quickly when exposed to the UV light in sunlight. Like other enveloped viruses, SARS-CoV-2 survives longest when the temperature is at room temperature or lower, and when the relative humidity is low (<50%).

 

On many surfaces, including as glass, some types of plastic, stainless steel, and skin, the virus can remain infective for several days indoors at room temperature, or even about a week under ideal conditions. On some surfaces, including cotton fabric and copper, the virus usually dies after a few hours. As a general rule of thumb, the virus dies faster on porous surfaces than on non-porous surfaces.

However, this rule is not absolute, and of the many surfaces tested, two with the longest survival times are N95 respirator masks and surgical masks, both of which are considered porous surfaces.

 

Surfaces may be decontaminated with 62–71 percent ethanol, 50–100 percent isopropanol, 0.1 percent sodium hypochlorite, 0.5 percent hydrogen peroxide, and 0.2–7.5 percent povidone-iodine. Other solutions, such as benzalkonium chloride and chlorhexidine gluconate, are less effective. Ultraviolet germicidal irradiation may also be used. The CDC recommends that if a COVID-19 case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons should be disinfected. A datasheet comprising the authorised substances to disinfection in the food industry (including suspension or surface tested, kind of surface, use dilution, disinfectant and inocuylum volumes) can be seen in the supplementary material of.

 

VENTILATION AND AIR FILTRATION

The WHO recommends ventilation and air filtration in public spaces to help clear out infectious aerosols.

 

HEALTHY DIET AND LIFESTYLE

The Harvard T.H. Chan School of Public Health recommends a healthy diet, being physically active, managing psychological stress, and getting enough sleep.

 

While there is no evidence that vitamin D is an effective treatment for COVID-19, there is limited evidence that vitamin D deficiency increases the risk of severe COVID-19 symptoms. This has led to recommendations for individuals with vitamin D deficiency to take vitamin D supplements as a way of mitigating the risk of COVID-19 and other health issues associated with a possible increase in deficiency due to social distancing.

 

TREATMENT

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus. Thus, the cornerstone of management of COVID-19 is supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.

 

Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.

 

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.

Several experimental treatments are being actively studied in clinical trials. Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful. Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment. Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy.

 

PROGNOSIS

The severity of COVID-19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. In 3–4% of cases (7.4% for those over age 65) symptoms are severe enough to cause hospitalization. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks. The Italian Istituto Superiore di Sanità reported that the median time between the onset of symptoms and death was twelve days, with seven being hospitalised. However, people transferred to an ICU had a median time of ten days between hospitalisation and death. Prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital are associated with severe course of COVID-19 and with a transfer to ICU.

 

Some early studies suggest 10% to 20% of people with COVID-19 will experience symptoms lasting longer than a month.[191][192] A majority of those who were admitted to hospital with severe disease report long-term problems including fatigue and shortness of breath. On 30 October 2020 WHO chief Tedros Adhanom warned that "to a significant number of people, the COVID virus poses a range of serious long-term effects". He has described the vast spectrum of COVID-19 symptoms that fluctuate over time as "really concerning." They range from fatigue, a cough and shortness of breath, to inflammation and injury of major organs – including the lungs and heart, and also neurological and psychologic effects. Symptoms often overlap and can affect any system in the body. Infected people have reported cyclical bouts of fatigue, headaches, months of complete exhaustion, mood swings, and other symptoms. Tedros has concluded that therefore herd immunity is "morally unconscionable and unfeasible".

 

In terms of hospital readmissions about 9% of 106,000 individuals had to return for hospital treatment within 2 months of discharge. The average to readmit was 8 days since first hospital visit. There are several risk factors that have been identified as being a cause of multiple admissions to a hospital facility. Among these are advanced age (above 65 years of age) and presence of a chronic condition such as diabetes, COPD, heart failure or chronic kidney disease.

 

According to scientific reviews smokers are more likely to require intensive care or die compared to non-smokers, air pollution is similarly associated with risk factors, and pre-existing heart and lung diseases and also obesity contributes to an increased health risk of COVID-19.

 

It is also assumed that those that are immunocompromised are at higher risk of getting severely sick from SARS-CoV-2. One research that looked into the COVID-19 infections in hospitalized kidney transplant recipients found a mortality rate of 11%.

See also: Impact of the COVID-19 pandemic on children

 

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years. They are likely to have milder symptoms and a lower chance of severe disease than adults. A European multinational study of hospitalized children published in The Lancet on 25 June 2020 found that about 8% of children admitted to a hospital needed intensive care. Four of those 582 children (0.7%) died, but the actual mortality rate could be "substantially lower" since milder cases that did not seek medical help were not included in the study.

 

Genetics also plays an important role in the ability to fight off the disease. For instance, those that do not produce detectable type I interferons or produce auto-antibodies against these may get much sicker from COVID-19. Genetic screening is able to detect interferon effector genes.

 

Pregnant women may be at higher risk of severe COVID-19 infection based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.

 

COMPLICATIONS

Complications may include pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, septic shock, and death. Cardiovascular complications may include heart failure, arrhythmias, heart inflammation, and blood clots. Approximately 20–30% of people who present with COVID-19 have elevated liver enzymes, reflecting liver injury.

 

Neurologic manifestations include seizure, stroke, encephalitis, and Guillain–Barré syndrome (which includes loss of motor functions). Following the infection, children may develop paediatric multisystem inflammatory syndrome, which has symptoms similar to Kawasaki disease, which can be fatal. In very rare cases, acute encephalopathy can occur, and it can be considered in those who have been diagnosed with COVID-19 and have an altered mental status.

 

LONGER-TERM EFFECTS

Some early studies suggest that that 10 to 20% of people with COVID-19 will experience symptoms lasting longer than a month. A majority of those who were admitted to hospital with severe disease report long-term problems, including fatigue and shortness of breath. About 5-10% of patients admitted to hospital progress to severe or critical disease, including pneumonia and acute respiratory failure.

 

By a variety of mechanisms, the lungs are the organs most affected in COVID-19.[228] The majority of CT scans performed show lung abnormalities in people tested after 28 days of illness.

 

People with advanced age, severe disease, prolonged ICU stays, or who smoke are more likely to have long lasting effects, including pulmonary fibrosis. Overall, approximately one third of those investigated after 4 weeks will have findings of pulmonary fibrosis or reduced lung function as measured by DLCO, even in people who are asymptomatic, but with the suggestion of continuing improvement with the passing of more time.

 

IMMUNITY

The immune response by humans to CoV-2 virus occurs as a combination of the cell-mediated immunity and antibody production, just as with most other infections. Since SARS-CoV-2 has been in the human population only since December 2019, it remains unknown if the immunity is long-lasting in people who recover from the disease. The presence of neutralizing antibodies in blood strongly correlates with protection from infection, but the level of neutralizing antibody declines with time. Those with asymptomatic or mild disease had undetectable levels of neutralizing antibody two months after infection. In another study, the level of neutralizing antibody fell 4-fold 1 to 4 months after the onset of symptoms. However, the lack of antibody in the blood does not mean antibody will not be rapidly produced upon reexposure to SARS-CoV-2. Memory B cells specific for the spike and nucleocapsid proteins of SARS-CoV-2 last for at least 6 months after appearance of symptoms. Nevertheless, 15 cases of reinfection with SARS-CoV-2 have been reported using stringent CDC criteria requiring identification of a different variant from the second infection. There are likely to be many more people who have been reinfected with the virus. Herd immunity will not eliminate the virus if reinfection is common. Some other coronaviruses circulating in people are capable of reinfection after roughly a year. Nonetheless, on 3 March 2021, scientists reported that a much more contagious Covid-19 variant, Lineage P.1, first detected in Japan, and subsequently found in Brazil, as well as in several places in the United States, may be associated with Covid-19 disease reinfection after recovery from an earlier Covid-19 infection.

 

MORTALITY

Several measures are commonly used to quantify mortality. These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health. The mortality rate reflects the number of deaths within a specific demographic group divided by the population of that demographic group. Consequently, the mortality rate reflects the prevalence as well as the severity of the disease within a given population. Mortality rates are highly correlated to age, with relatively low rates for young people and relatively high rates among the elderly.

 

The case fatality rate (CFR) reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 2.2% (2,685,770/121,585,388) as of 18 March 2021. The number varies by region. The CFR may not reflect the true severity of the disease, because some infected individuals remain asymptomatic or experience only mild symptoms, and hence such infections may not be included in official case reports. Moreover, the CFR may vary markedly over time and across locations due to the availability of live virus tests.

 

INFECTION FATALITY RATE

A key metric in gauging the severity of COVID-19 is the infection fatality rate (IFR), also referred to as the infection fatality ratio or infection fatality risk. This metric is calculated by dividing the total number of deaths from the disease by the total number of infected individuals; hence, in contrast to the CFR, the IFR incorporates asymptomatic and undiagnosed infections as well as reported cases.

 

CURRENT ESTIMATES

A December 2020 systematic review and meta-analysis estimated that population IFR during the first wave of the pandemic was about 0.5% to 1% in many locations (including France, Netherlands, New Zealand, and Portugal), 1% to 2% in other locations (Australia, England, Lithuania, and Spain), and exceeded 2% in Italy. That study also found that most of these differences in IFR reflected corresponding differences in the age composition of the population and age-specific infection rates; in particular, the metaregression estimate of IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. These results were also highlighted in a December 2020 report issued by the WHO.

 

EARLIER ESTIMATES OF IFR

At an early stage of the pandemic, the World Health Organization reported estimates of IFR between 0.3% and 1%.[ On 2 July, The WHO's chief scientist reported that the average IFR estimate presented at a two-day WHO expert forum was about 0.6%. In August, the WHO found that studies incorporating data from broad serology testing in Europe showed IFR estimates converging at approximately 0.5–1%. Firm lower limits of IFRs have been established in a number of locations such as New York City and Bergamo in Italy since the IFR cannot be less than the population fatality rate. As of 10 July, in New York City, with a population of 8.4 million, 23,377 individuals (18,758 confirmed and 4,619 probable) have died with COVID-19 (0.3% of the population).Antibody testing in New York City suggested an IFR of ~0.9%,[258] and ~1.4%. In Bergamo province, 0.6% of the population has died. In September 2020 the U.S. Center for Disease Control & Prevention reported preliminary estimates of age-specific IFRs for public health planning purposes.

 

SEX DIFFERENCES

Early reviews of epidemiologic data showed gendered impact of the pandemic and a higher mortality rate in men in China and Italy. The Chinese Center for Disease Control and Prevention reported the death rate was 2.8% for men and 1.7% for women. Later reviews in June 2020 indicated that there is no significant difference in susceptibility or in CFR between genders. One review acknowledges the different mortality rates in Chinese men, suggesting that it may be attributable to lifestyle choices such as smoking and drinking alcohol rather than genetic factors. Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men. In Europe, 57% of the infected people were men and 72% of those died with COVID-19 were men. As of April 2020, the US government is not tracking sex-related data of COVID-19 infections. Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.

 

ETHNIC DIFFERENCES

In the US, a greater proportion of deaths due to COVID-19 have occurred among African Americans and other minority groups. Structural factors that prevent them from practicing social distancing include their concentration in crowded substandard housing and in "essential" occupations such as retail grocery workers, public transit employees, health-care workers and custodial staff. Greater prevalence of lacking health insurance and care and of underlying conditions such as diabetes, hypertension and heart disease also increase their risk of death. Similar issues affect Native American and Latino communities. According to a US health policy non-profit, 34% of American Indian and Alaska Native People (AIAN) non-elderly adults are at risk of serious illness compared to 21% of white non-elderly adults. The source attributes it to disproportionately high rates of many health conditions that may put them at higher risk as well as living conditions like lack of access to clean water. Leaders have called for efforts to research and address the disparities. In the U.K., a greater proportion of deaths due to COVID-19 have occurred in those of a Black, Asian, and other ethnic minority background. More severe impacts upon victims including the relative incidence of the necessity of hospitalization requirements, and vulnerability to the disease has been associated via DNA analysis to be expressed in genetic variants at chromosomal region 3, features that are associated with European Neanderthal heritage. That structure imposes greater risks that those affected will develop a more severe form of the disease. The findings are from Professor Svante Pääbo and researchers he leads at the Max Planck Institute for Evolutionary Anthropology and the Karolinska Institutet. This admixture of modern human and Neanderthal genes is estimated to have occurred roughly between 50,000 and 60,000 years ago in Southern Europe.

 

COMORBIDITIES

Most of those who die of COVID-19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease. According to March data from the United States, 89% of those hospitalised had preexisting conditions. The Italian Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available, 96.1% of people had at least one comorbidity with the average person having 3.4 diseases. According to this report the most common comorbidities are hypertension (66% of deaths), type 2 diabetes (29.8% of deaths), Ischemic Heart Disease (27.6% of deaths), atrial fibrillation (23.1% of deaths) and chronic renal failure (20.2% of deaths).

 

Most critical respiratory comorbidities according to the CDC, are: moderate or severe asthma, pre-existing COPD, pulmonary fibrosis, cystic fibrosis. Evidence stemming from meta-analysis of several smaller research papers also suggests that smoking can be associated with worse outcomes. When someone with existing respiratory problems is infected with COVID-19, they might be at greater risk for severe symptoms. COVID-19 also poses a greater risk to people who misuse opioids and methamphetamines, insofar as their drug use may have caused lung damage.

 

In August 2020 the CDC issued a caution that tuberculosis infections could increase the risk of severe illness or death. The WHO recommended that people with respiratory symptoms be screened for both diseases, as testing positive for COVID-19 couldn't rule out co-infections. Some projections have estimated that reduced TB detection due to the pandemic could result in 6.3 million additional TB cases and 1.4 million TB related deaths by 2025.

 

NAME

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as "coronavirus" and "Wuhan coronavirus", with the disease sometimes called "Wuhan pneumonia". In the past, many diseases have been named after geographical locations, such as the Spanish flu, Middle East Respiratory Syndrome, and Zika virus. In January 2020, the WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species, or groups of people in disease and virus names in part to prevent social stigma. The official names COVID-19 and SARS-CoV-2 were issued by the WHO on 11 February 2020. Tedros Adhanom explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019). The WHO additionally uses "the COVID-19 virus" and "the virus responsible for COVID-19" in public communications.

 

HISTORY

The virus is thought to be natural and of an animal origin, through spillover infection. There are several theories about where the first case (the so-called patient zero) originated. Phylogenetics estimates that SARS-CoV-2 arose in October or November 2019. Evidence suggests that it descends from a coronavirus that infects wild bats, and spread to humans through an intermediary wildlife host.

 

The first known human infections were in Wuhan, Hubei, China. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as 1 December 2019.Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019. Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020. According to official Chinese sources, these were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals. In May 2020 George Gao, the director of the CDC, said animal samples collected from the seafood market had tested negative for the virus, indicating that the market was the site of an early superspreading event, but that it was not the site of the initial outbreak.[ Traces of the virus have been found in wastewater samples that were collected in Milan and Turin, Italy, on 18 December 2019.

 

By December 2019, the spread of infection was almost entirely driven by human-to-human transmission. The number of coronavirus cases in Hubei gradually increased, reaching 60 by 20 December, and at least 266 by 31 December. On 24 December, Wuhan Central Hospital sent a bronchoalveolar lavage fluid (BAL) sample from an unresolved clinical case to sequencing company Vision Medicals. On 27 and 28 December, Vision Medicals informed the Wuhan Central Hospital and the Chinese CDC of the results of the test, showing a new coronavirus. A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December. On 30 December, a test report addressed to Wuhan Central Hospital, from company CapitalBio Medlab, stated an erroneous positive result for SARS, causing a group of doctors at Wuhan Central Hospital to alert their colleagues and relevant hospital authorities of the result. The Wuhan Municipal Health Commission issued a notice to various medical institutions on "the treatment of pneumonia of unknown cause" that same evening. Eight of these doctors, including Li Wenliang (punished on 3 January), were later admonished by the police for spreading false rumours and another, Ai Fen, was reprimanded by her superiors for raising the alarm.

 

The Wuhan Municipal Health Commission made the first public announcement of a pneumonia outbreak of unknown cause on 31 December, confirming 27 cases—enough to trigger an investigation.

 

During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange. On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen. Later official data shows 6,174 people had already developed symptoms by then, and more may have been infected. A report in The Lancet on 24 January indicated human transmission, strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its "pandemic potential". On 30 January, the WHO declared the coronavirus a Public Health Emergency of International Concern. By this time, the outbreak spread by a factor of 100 to 200 times.

 

Italy had its first confirmed cases on 31 January 2020, two tourists from China. As of 13 March 2020 the WHO considered Europe the active centre of the pandemic. Italy overtook China as the country with the most deaths on 19 March 2020. By 26 March the United States had overtaken China and Italy with the highest number of confirmed cases in the world. Research on coronavirus genomes indicates the majority of COVID-19 cases in New York came from European travellers, rather than directly from China or any other Asian country. Retesting of prior samples found a person in France who had the virus on 27 December 2019, and a person in the United States who died from the disease on 6 February 2020.

 

After 55 days without a locally transmitted case, Beijing reported a new COVID-19 case on 11 June 2020 which was followed by two more cases on 12 June. By 15 June there were 79 cases officially confirmed, most of them were people that went to Xinfadi Wholesale Market.

 

RT-PCR testing of untreated wastewater samples from Brazil and Italy have suggested detection of SARS-CoV-2 as early as November and December 2019, respectively, but the methods of such sewage studies have not been optimised, many have not been peer reviewed, details are often missing, and there is a risk of false positives due to contamination or if only one gene target is detected. A September 2020 review journal article said, "The possibility that the COVID-19 infection had already spread to Europe at the end of last year is now indicated by abundant, even if partially circumstantial, evidence", including pneumonia case numbers and radiology in France and Italy in November and December.

 

MISINFORMATION

After the initial outbreak of COVID-19, misinformation and disinformation regarding the origin, scale, prevention, treatment, and other aspects of the disease rapidly spread online.

 

In September 2020, the U.S. CDC published preliminary estimates of the risk of death by age groups in the United States, but those estimates were widely misreported and misunderstood.

 

OTHER ANIMALS

Humans appear to be capable of spreading the virus to some other animals, a type of disease transmission referred to as zooanthroponosis.

 

Some pets, especially cats and ferrets, can catch this virus from infected humans. Symptoms in cats include respiratory (such as a cough) and digestive symptoms. Cats can spread the virus to other cats, and may be able to spread the virus to humans, but cat-to-human transmission of SARS-CoV-2 has not been proven. Compared to cats, dogs are less susceptible to this infection. Behaviors which increase the risk of transmission include kissing, licking, and petting the animal.

 

The virus does not appear to be able to infect pigs, ducks, or chickens at all.[ Mice, rats, and rabbits, if they can be infected at all, are unlikely to be involved in spreading the virus.

 

Tigers and lions in zoos have become infected as a result of contact with infected humans. As expected, monkeys and great ape species such as orangutans can also be infected with the COVID-19 virus.

 

Minks, which are in the same family as ferrets, have been infected. Minks may be asymptomatic, and can also spread the virus to humans. Multiple countries have identified infected animals in mink farms. Denmark, a major producer of mink pelts, ordered the slaughter of all minks over fears of viral mutations. A vaccine for mink and other animals is being researched.

 

RESEARCH

International research on vaccines and medicines in COVID-19 is underway by government organisations, academic groups, and industry researchers. The CDC has classified it to require a BSL3 grade laboratory. There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand.

 

As of December 2020, hundreds of clinical trials have been undertaken, with research happening on every continent except Antarctica. As of November 2020, more than 200 possible treatments had been studied in humans so far.

Transmission and prevention research

Modelling research has been conducted with several objectives, including predictions of the dynamics of transmission, diagnosis and prognosis of infection, estimation of the impact of interventions, or allocation of resources. Modelling studies are mostly based on epidemiological models, estimating the number of infected people over time under given conditions. Several other types of models have been developed and used during the COVID-19 including computational fluid dynamics models to study the flow physics of COVID-19, retrofits of crowd movement models to study occupant exposure, mobility-data based models to investigate transmission, or the use of macroeconomic models to assess the economic impact of the pandemic. Further, conceptual frameworks from crisis management research have been applied to better understand the effects of COVID-19 on organizations worldwide.

 

TREATMENT-RELATED RESEARCH

Repurposed antiviral drugs make up most of the research into COVID-19 treatments. Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.

 

In March 2020, the World Health Organization (WHO) initiated the Solidarity trial to assess the treatment effects of some promising drugs: an experimental drug called remdesivir; anti-malarial drugs chloroquine and hydroxychloroquine; two anti-HIV drugs, lopinavir/ritonavir; and interferon-beta. More than 300 active clinical trials were underway as of April 2020.

 

Research on the antimalarial drugs hydroxychloroquine and chloroquine showed that they were ineffective at best, and that they may reduce the antiviral activity of remdesivir. By May 2020, France, Italy, and Belgium had banned the use of hydroxychloroquine as a COVID-19 treatment.

 

In June, initial results from the randomised RECOVERY Trial in the United Kingdom showed that dexamethasone reduced mortality by one third for people who are critically ill on ventilators and one fifth for those receiving supplemental oxygen. Because this is a well-tested and widely available treatment, it was welcomed by the WHO, which is in the process of updating treatment guidelines to include dexamethasone and other steroids. Based on those preliminary results, dexamethasone treatment has been recommended by the NIH for patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen but not in patients with COVID-19 who do not require supplemental oxygen.

 

In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19. The WHO recommends systemic corticosteroids rather than no systemic corticosteroids for the treatment of people with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). The WHO suggests not to use corticosteroids in the treatment of people with non-severe COVID-19 (conditional recommendation, based on low certainty evidence). The updated guidance was based on a meta-analysis of clinical trials of critically ill COVID-19 patients.

 

WIKIPEDIA

Candibiotic

Thuốc nhỏ tai

Thành phần :

Cloramphenicol BP 5%

Beclometasone Dipropionate BP 0.025%

Clotrimazole USP 1%

Lidocaine Hydrochloride BP 2%

Glycerin BP Vừa đủ

Propylene Glycol USP Vừa đủ

Cơ chế tác động :

Cloramphenicol :

Cloramphenicol là kháng sinh có phổ kháng khuẩn rộng bao gồm cả vi khuẩn Gr(+), Gr(-), và hiệu quả cao đối với vi khuẩn kỵ khí. Cơ chế tác động là ức chế sinh tổng hợp protein của màng tế bào vi khuẩn.

Beclometasone Dipropionate :

Beclometasone có tính kháng viêm tại chỗ mạnh, ít tác dụng phụ (như ức chế vỏ thuợng thận hơn, lóet dạ dày tá tràng, giữ nước ) hơn các Glucocorticoid khác, hạn chế tối thiểu tác dụng phụ ton thân.

Clotrimazole :

Clotrimazole là thuốc kháng nấm nhóm Imidazole, tác động bằng cách ức mạnh và đặc hiệu đối với sự tổng hợp esgosterol của nấm, dẫn đến sự rối lọan chức năng màng và ức chế nấm tăng trưởng, diệt nấm. Hiệu quả, an tòan hơn các Imidazole khác.

Lidocain :

Lidocain là chất gy tê tại chỗ, làm mất cảm giác đau tại nơi tiếp xúc, tác động nhanh, mạnh, thời gian tc dụng kéo dài ít nhất là 6 giờ. Tác dụng gy tê hồi phục hồn ton.

* Sự phối hợp của các thành phần trên cho một tác dụng tòan diện, điều trị viêm nhiễm tai do nhiều nguyên nhân như nấm, vi khuẩn…

Chỉ định :

Các trường hợp viêm và dị ứng tai. Chảy dịch tai, sáp tai, nhiễm trùng hay nhiễm nấm tai giữa và tai ngòai. Phẫu thuật xương chủm.

Chống chỉ định :

Mẫn cảm với bất kỳ thành phần nào của thuốc.

Liều lượng và cách dùng :

Nhỏ tai 4-5 giọt/lần x 3-4 lần/ngày.

Tác dụng phụ :

Thỉnh thoảng gặp trường hợp kích ứng tại chỗ như ngứa hay rát.

Thận trọng :

Ngưng dùng thuốc khi có triệu chứng kích ứng tại chỗ kéo dài.

Tương tác thuốc :

-Không có báo cáo về tương tác thuốc với Clotrimazole, Beclometasone dipropionate.

-Sử dụng đồng thời Cimetidine ở bệnh nhân đang dùng Lidocain có thể dẫn đến tăng nồng độ Lidocain trong huyết tương và tăng độc tính.

-Propanolol làm giảm độ thanh thải Lidocain.

-Không nên dùng đồng thời Chloramphenicol với các kháng sinh như

( penicillin, cephalosporins, gentamicin, tetracycline, polymixin B, vancomycin, sulfadiazine ) vì những thuốc này làm giảm tác động kháng khuẩn của Cloramphenicol.

-Không nên dùng đồng thời Chloramphenicol với các thuốc gy tác dụng phụ trên hệ tạo máu hay với sulfonylurea, dẫn chất coumarin, hydantoin và methotrexate.

Bảo quản :

Bảo quản nơi thống mát, tránh ánh sáng, nhiệt độ dưới 250C.

Dạng trình bày : Chai 5 ml.

  

ĐỌC KỸ HƯỚNG DẪN TRƯỚC KHI DÙNG.

NẾU CẦN THÔNG TIN XIN HỎI Ý KIẾN THẦY THUỐC.

ĐỂ THUỐC TRÁNH KHỎI TẦM TAY TRẺ EM.

VISA N0 : VN-3640-07

  

Nhà sản xuất :

……

 

HƯỚNG DẪN SỬ DỤNG :

1.Tháo nt bằng kim lọai của chai thuốc.

2.Đặt bộ phận nhỏ giọt vào đầu chai và vặn theo chiều kim đồng hồ.

3.Nhỏ thuốc vào tai bị bệnh theo chỉ định của Thầy thuốc.

4.Đặt trở lại bộ phận nhỏ giọt vào chai thuốc.

                              

Làm brochure :

Candibiotic

Thuốc nhỏ tai

Thành phần :

Cloramphenicol BP 5%

Beclometasone Dipropionate BP 0.025%

Clotrimazole USP 1%

Lidocaine Hydrochloride BP 2%

Glycerin BP Vừa đủ

Propylene Glycol USP Vừa đủ

Cơ chế tác động :

Cloramphenicol :

Cloramphenicol là kháng sinh có phổ kháng khuẩn rộng bao gồm cả vi khuẩn Gr(+), Gr(-), và hiệu quả cao đối với vi khuẩn kỵ khí. Cơ chế tác động là ức chế sinh tổng hợp protein của màng tế bào vi khuẩn.

Beclometasone Dipropionate :

Beclometasone có tính kháng viêm tại chỗ mạnh, ít tác dụng phụ (như ức chế vỏ thuợng thận hơn, lot dạ dày tá tràng, giữ nước ) hơn các Glucocorticoid khác, hạn chế tối thiểu tác dụng phụ tồn thân.

Clotrimazole :

Clotrimazole là thuốc kháng nấm nhóm Imidazole, tác động bằng cách ức mạnh và đặc hiệu đối với sự tổng hợp esgosterol của nấm, dẫn đến sự rối lọan chức năng màng và ức chế nấm tăng trưởng, diệt nấm. Hiệu quả, an toàn hơn các Imidazole khác.

Lidocain :

Lidocain là chất gy tê tại chỗ, làm mất cảm giác đau tại nơi tiếp xúc, tác động nhanh, mạnh, thời gian dụng kéo dài ít nhất là 6 giờ. Tác dụng gy tê hồi phục hon ton.

Glycerin & Propylen Glycol :

Tác dụng như chất hòa tan sáp tai, và có tính sát khuẩn.

* Sự phối hợp của các thành phần trên cho một tác dụng tòan diện, điều trị viêm nhiễm tai do nhiều nguyên nhân như nấm, vi khuẩn…

Chỉ định : Candibiotic được chỉ định trong :

Các trường hợp viêm và dị ứng tai.

Chảy dịch tai.

Nhiễm trùng hay nhiễm nấm tai giữa và tai ngòai.

Làm sáp tai tiêu đi hay bong tróc dễ dàng, rất thuận tiện cho trẻ em.

Phẫu thuật xương chủm.

Chống chỉ định :

Mẫn cảm với bất kỳ thành phần nào của thuốc.

Liều lượng và cách dùng :

Nhỏ tai 4-5 giọt/lần x 3-4 lần/ngày, tùy theo chỉ định của Thầy thuốc

Tác dụng phụ : Hiếm khi mới gặp trường hợp kích ứng tại chỗ như ngứa hay rát.

Thận trọng : Ngưng dùng thuốc khi có triệu chứng kích ứng tại chỗ kéo dài.

Bảo quản : Bảo quản nơi mát, tránh ánh sáng, nhiệt độ dưới 250C

I take a few dozen pills at various times throughout the day. It can be difficult to keep track of it all. I wake up and must eat food first for the dexamethasone. That's an artificial steroid (actually glucocorticoid steroid) that keeps the swelling in my brain down. It's the most important med in my fold-out aluminium case. It's also the most side-effect packed - among other things it's weakened my leg muscles, left me bloated and overweight and disrupted my sleep intensely. And I have to take other pills to protect my stomach and my bones from its effects.

 

A major knock-on of the weight gain seems to be back problems on top of myopathy (the degradation of my muscles). So I'm on a lot of painkillers. Oxycontin, Pregabalin and good old paracetamol. I take a lot and still need Oxynorm for 'breakthrough pain' - the stuff that wakes me in the night.

 

There's the anti-seizure pills too. I've been having little seizures once in a while as a follow-up to December's Grand Mal which left me on life-support for a short while. These ones aren't very bad, and often I have an 'aura' or flashing lights, so I take a lorezapam under the tongue immediately. And prophylactically, I take clobazam and Phenytoin. Susan also carries a bottle of midolazam and an oral syringe in case I have another Grand Mal seizure.

 

Susan has created a spreadsheet of times and doses of all of these and more. She's made labels for all the compartments in the open-out case. And she co-ordinates between the hospice, the GP and the chemists when it all runs out.

 

And so here I am. My morning dose of dexamethasone, omeprazole and paracetamol, washed down with movicol powder (did I mention the digestion gets screwed up too?). I'm in the middle of my first Temadol chemotherapy cycle. In 10 days, I will be adding four more pills a day. Temadol, aka Temazolomide, a chemo drug that will hopefully shrink my 19 (last count) brain lesions. I take that drug for 5 days along with some very strong anti-nausea pills. Then, wait two weeks and we have an MRI look at my brain. See what the Gamma Knife Surgery and two rounds of chemo have achieved.

 

For the shot, I put up one of my Esprit Gemini 250ws strobes with a 40cm Beauty Dish on it to the front right and a medium round, silver reflector propped up to the left. I put my M9 with the Voigtlander 35mm f1.2 Nokton Aspherical on a tripod in front of me and put it on self-time. The shots looked well-light on the camera display, but were dark in Lightroom, so I adjusted accordingly. I had Diego Velazquez in mind in composing, lighting and post-processing. I hope this comes across somehow.

I take a few dozen pills at various times throughout the day. It can be difficult to keep track of it all. I wake up and must eat food first for the dexamethasone. That's an artificial steroid (actually glucocorticoid steroid) that keeps the swelling in my brain down. It's the most important med in my fold-out aluminium case. It's also the most side-effect packed - among other things it's weakened my leg muscles, left me bloated and overweight and disrupted my sleep intensely. And I have to take other pills to protect my stomach and my bones from its effects.

 

A major knock-on of the weight gain seems to be back problems on top of myopathy (the degradation of my muscles). So I'm on a lot of painkillers. Oxycontin, Pregabalin and good old paracetamol. I take a lot and still need Oxynorm for 'breakthrough pain' - the stuff that wakes me in the night.

 

There's the anti-seizure pills too. I've been having little seizures once in a while as a follow-up to December's Grand Mal which left me on life-support for a short while. These ones aren't very bad, and often I have an 'aura' or flashing lights, so I take a lorezapam under the tongue immediately. And prophylactically, I take clobazam and Phenytoin. Susan also carries a bottle of midolazam and an oral syringe in case I have another Grand Mal seizure.

 

Susan has created a spreadsheet of times and doses of all of these and more. She's made labels for all the compartments in the open-out case. And she co-ordinates between the hospice, the GP and the chemists when it all runs out.

 

And so here I am. My morning dose of dexamethasone, omeprazole and paracetamol, washed down with movicol powder (did I mention the digestion gets screwed up too?). I'm in the middle of my first Temadol chemotherapy cycle. In 10 days, I will be adding four more pills a day. Temadol, aka Temazolomide, a chemo drug that will hopefully shrink my 19 (last count) brain lesions. I take that drug for 5 days along with some very strong anti-nausea pills. Then, wait two weeks and we have an MRI look at my brain. See what the Gamma Knife Surgery and two rounds of chemo have achieved.

 

For the shot, I put up one of my Esprit Gemini 250ws strobes with a 40cm Beauty Dish on it to the front right and a medium round, silver reflector propped up to the left. I put my M9 with the Voigtlander 35mm f1.2 Nokton Aspherical on a tripod in front of me and put it on self-time. The shots looked well-light on the camera display, but were dark in Lightroom, so I adjusted accordingly. I had Diego Velazquez in mind in composing, lighting and post-processing. I hope this comes across somehow.

I take a few dozen pills at various times throughout the day. It can be difficult to keep track of it all. I wake up and must eat food first for the dexamethasone. That's an artificial steroid (actually glucocorticoid steroid) that keeps the swelling in my brain down. It's the most important med in my fold-out aluminium case. It's also the most side-effect packed - among other things it's weakened my leg muscles, left me bloated and overweight and disrupted my sleep intensely. And I have to take other pills to protect my stomach and my bones from its effects.

 

A major knock-on of the weight gain seems to be back problems on top of myopathy (the degradation of my muscles). So I'm on a lot of painkillers. Oxycontin, Pregabalin and good old paracetamol. I take a lot and still need Oxynorm for 'breakthrough pain' - the stuff that wakes me in the night.

 

There's the anti-seizure pills too. I've been having little seizures once in a while as a follow-up to December's Grand Mal which left me on life-support for a short while. These ones aren't very bad, and often I have an 'aura' or flashing lights, so I take a lorezapam under the tongue immediately. And prophylactically, I take clobazam and Phenytoin. Susan also carries a bottle of midolazam and an oral syringe in case I have another Grand Mal seizure.

 

Susan has created a spreadsheet of times and doses of all of these and more. She's made labels for all the compartments in the open-out case. And she co-ordinates between the hospice, the GP and the chemists when it all runs out.

 

And so here I am. My morning dose of dexamethasone, omeprazole and paracetamol, washed down with movicol powder (did I mention the digestion gets screwed up too?). I'm in the middle of my first Temadol chemotherapy cycle. In 10 days, I will be adding four more pills a day. Temadol, aka Temazolomide, a chemo drug that will hopefully shrink my 19 (last count) brain lesions. I take that drug for 5 days along with some very strong anti-nausea pills. Then, wait two weeks and we have an MRI look at my brain. See what the Gamma Knife Surgery and two rounds of chemo have achieved.

 

For the shot, I put up one of my Esprit Gemini 250ws strobes with a 40cm Beauty Dish on it to the front right and a medium round, silver reflector propped up to the left. I put my M9 with the Voigtlander 35mm f1.2 Nokton Aspherical on a tripod in front of me and put it on self-time. The shots looked well-light on the camera display, but were dark in Lightroom, so I adjusted accordingly. I had Diego Velazquez in mind in composing, lighting and post-processing. I hope this comes across somehow.

I take a few dozen pills at various times throughout the day. It can be difficult to keep track of it all. I wake up and must eat food first for the dexamethasone. That's an artificial steroid (actually glucocorticoid steroid) that keeps the swelling in my brain down. It's the most important med in my fold-out aluminium case. It's also the most side-effect packed - among other things it's weakened my leg muscles, left me bloated and overweight and disrupted my sleep intensely. And I have to take other pills to protect my stomach and my bones from its effects.

 

A major knock-on of the weight gain seems to be back problems on top of myopathy (the degradation of my muscles). So I'm on a lot of painkillers. Oxycontin, Pregabalin and good old paracetamol. I take a lot and still need Oxynorm for 'breakthrough pain' - the stuff that wakes me in the night.

 

There's the anti-seizure pills too. I've been having little seizures once in a while as a follow-up to December's Grand Mal which left me on life-support for a short while. These ones aren't very bad, and often I have an 'aura' or flashing lights, so I take a lorezapam under the tongue immediately. And prophylactically, I take clobazam and Phenytoin. Susan also carries a bottle of midolazam and an oral syringe in case I have another Grand Mal seizure.

 

Susan has created a spreadsheet of times and doses of all of these and more. She's made labels for all the compartments in the open-out case. And she co-ordinates between the hospice, the GP and the chemists when it all runs out.

 

And so here I am. My morning dose of dexamethasone, omeprazole and paracetamol, washed down with movicol powder (did I mention the digestion gets screwed up too?). I'm in the middle of my first Temadol chemotherapy cycle. In 10 days, I will be adding four more pills a day. Temadol, aka Temazolomide, a chemo drug that will hopefully shrink my 19 (last count) brain lesions. I take that drug for 5 days along with some very strong anti-nausea pills. Then, wait two weeks and we have an MRI look at my brain. See what the Gamma Knife Surgery and two rounds of chemo have achieved.

 

For the shot, I put up one of my Esprit Gemini 250ws strobes with a 40cm Beauty Dish on it to the front right and a medium round, silver reflector propped up to the left. I put my M9 with the Voigtlander 35mm f1.2 Nokton Aspherical on a tripod in front of me and put it on self-time. The shots looked well-light on the camera display, but were dark in Lightroom, so I adjusted accordingly. I had Diego Velazquez in mind in composing, lighting and post-processing. I hope this comes across somehow.

From here:

 

All cell types within the body express different genes/proteins that serve the cell’s function. Since a muscle cell has a completely different function than a skin cell, it will naturally express different proteins. In like manner, a 1 week-old neuron is functionally distinct from a 4 week-old neuron and the two will also express different proteins (to some extent). Many people have taken advantage of this, using these different proteins as markers that identify a new cell as a neuron vs. a glial cell or, more specifically, an immature neuron vs. a mature neuron. By simultaneously visualizing (via immunohistochemistry) both the birthdating marker (e.g. BrdU) and these phenotypic markers, one can know both the exact age of the neuron and its general degree of maturity. For a 10 sec guide to cell labeling with BrdU and phenotypic markers, see here.

 

What do these expression timecourses tell us?

 

some markers (proteins) are increasingly expressed as new neurons mature over 4 weeks (NSE, NeuN, calbindin)

other markers are mainly expressed when new neurons are < 4 weeks-old (DCX, PSA-NCAM, calretinin)

most studies have used the same markers (e.g. DCX, NeuN) to simply demonstrate that new cells are neurons, but some have examined expression of markers that are associated with a more specific function, such as glucocorticoid receptors (Cameron 1993, Garcia 2004) or vascular markers (Palmer 2000)

BrdU (or other birthdating markers) labeled cells express cell division markers (e.g. Ki67) several days after BrdU is administered. This does not mean newborn neurons are dividing – what it represents is the continued division of the stem cell, or precursor cell, that was originally labelled. (therefore you can never know the exact age of a new cell, but pretty close)

El asma es una enfermedad crónica del sistema respiratorio caracterizada por vías aéreas hiperreactivas, es decir, un incremento en la respuesta broncoconstrictora del árbol bronquial. Las vías aéreas más finas disminuyen ocasional y reversiblemente de calibre por contraerse su musculatura lisa o por ensanchamiento de su mucosa al inflamarse y producir mucosidad,por lo general en respuesta a uno o más factores desencadenantes como la exposición a un medio ambiente inadecuado (frio, húmedo o alergénico), el ejercicio o esfuerzo en pacientes hiper-reactivos, o el estrés emocional. En los niños los desencadenantes más frecuentes son las enfermedades comunes como aquellas que causan el resfriado común.

 

Ese estrechamiento causa obstrucción y por tanto dificultad para pasar el aire que es en gran parte reversible, a diferencia de la bronquitis crónica donde hay escasa reversibilidad. Cuando los síntomas del asma empeoran, se produce una crisis de asma. Por lo general son crisis respiratorias de corta duración, aunque puede haber períodos con ataques asmáticos diarios que pueden persistir por varias semanas. En una crisis severa, las vías respiratorias pueden cerrarse tanto que los órganos vitales no reciben suficiente oxígeno. En esos casos, la crisis asmática puede provocar la muerte.

 

El asma provoca síntomas tales como respiración sibilante, falta de aire (polipnea y taquipnea), opresión en el pecho y tos improductiva durante la noche o temprano en la mañana.Entre las exacerbaciones se intercalan períodos asintomáticos donde la mayoría de los pacientes se sienten bien, pero pueden tener síntomas leves, como permanecer sin aliento - después de hacer ejercicio - durante períodos más largos de tiempo que un individuo no afectado, que se recupera antes. Los síntomas del asma, que pueden variar desde algo leve hasta poner en peligro la vida, normalmente pueden ser controlados con una combinación de fármacos y cambios ambientales pues la constricción de las vías aéreas suele responder bien a los modernos broncodilatadores.

 

Los síntomas más característicos del asma bronquial son la disnea o dificultad respiratoria de intensidad y duración variable y con la presencia de espasmos bronquiales, habitualmente acompañados de tos, secreciones mucosas y respiración sibilante. En algunos pacientes estos síntomas persisten a un nivel bajo, mientras que en otros, los síntomas pueden ser severos y durar varios días o semanas. Bajo condiciones más severas, las funciones ventilatorias pulmonares pueden verse alteradas y causar cianosis e incluso la muerte

 

El tratamiento convencional del asma bronquial puede ser:[

 

* Sintomático. Tiene por objeto interrumpir la crisis mediante medicamentos de acción rápida, como la adrenalina, corticoides, oxigenoterapia, etc.

* Preventivo. Indica el uso regular de broncodilatadores, antihistamínicos, corticosteroides, terapia respiratoria, inmunoterapia específica, etc.

 

El tratamiento más eficaz para el asma se basa en la identificación de los elementos que inicien la crisis, tales como mascotas o la aspirina y limitando o, de ser posible, eliminando la exposición a dichos factores. Si resulta insuficiente evitar los factores estimulantes, entonces se puede recurrir al tratamiento médico. La desensitización es, por el momento, la única cura disponible para esta enfermedad.Otras formas de tratamiento incluyen el alivio farmacológico, los medicamentos de prevención, los agonistas de larga acción de los receptores β2, y el tratamiento de emergencia.

 

Tratamiento médico:

 

El tratamiento farmacológico específico recomendado para pacientes con asma depende en la severidad de su enfermedad y la frecuencia en la aparición de los síntomas. Los tratamientos específicos para el asma se clasifican a groso modo en medicinas preventivas y de emergencia. El reporte EPR-2 (por sus siglas en inglés Expert Panel Report 2), un protocolo para el diagnóstico y manejo del asma, así como el reporte de otras sociedades internacionales son usados y apoyados por muchos médicos.

 

Los broncodilatadores se recomiendan para el alivio a corto plazo en prácticamente todos los pacientes con asma. Para quienes tienen solo ataques ocasionales, no se necesita otro tipo de medicamento. Para quienes tienen una persistencia de los síntomas de manera moderada, es decir, más de dos crisis por semana, se sugieren glucocorticoides inhalados de baja concentración o, alternativamente, se puede administrar un modificador de leucotrienos oral, un estabilizador de la membrana de los mastocitos o la teofilina. Para los individuos que presenten crisis diarias, se sugiere una dosis más elevada de glucorticoides en conjunto con agonistas β-2 de larga acción inhalados o bien un modificador de los leucotrienos o la teofilina, pueden sustituir al agonista β-2. En los ataques asmáticos severos, se puede añadir glucocorticoides orales a estos tratamientos durante las crisis severas.

 

El descubrimiento en el año 2006 de que el asma puede ser causado por la sobre-proliferación de un tipo especial de linfocito NK puede conllevar ultimadamente al desarrollo de un mejor y más específico grupo de medicamentos. Los linfocitos T del grupo NK parece ser resistente a los corticosteroides, una de las principales líneas de tratamiento actual. Otras prometedoras opciones en estadíos de investigación incluyen el uso de estatinas, que son medicamentos que disminuyen el nivel de colesterol en el plasma sanguíneo y el uso de suplementos con aceite de pescado, para reducir la inflamación en las vías respiratorias

 

Nebulizadores:

Inhalador clásico de salmeterol, un broncodilatador.

 

Los nebulizadores proveen una dosis más continua y duradera al vaporizar la medicina diluida en solución salina, el cual el paciente inhala hasta que se administra la dosis completa. No hay evidencias de que sean más efectivas que un spacer. El alivio de crisis asmáticas incluye medicamentos:

 

* Agonistas de los receptores adrenérgicos beta2 de corta duración, tales como el salbutamol, levalbuterol, terbutalina y bitolterol. Los efectos secundarios que incluía la aparición de temblores, se han reducido grandemente con los tratamientos inhalados, que permite que el medicamento haga blanco específicamente en los pulmones. Los medicamentos que son administrados por vía oral o inyectados tienden a ser distribuidos por el resto del cuerpo, aumentando la posibilidad de la aparición de los efectos adversos, incluyendo efectos cardíacos por actividad agonista de los receptores beta1 que causan hipertensión arterial y trastornos del ritmo cardíaco. Con la salida al mercado de fármacos más selectivos, estos efectos secundarios se han vuelto menos frecuentes. Los agonistas de los receptores adrenérgicos beta2 suelen producir desensitación en el paciente, por lo que su eficacia puede disminuir con su uso crónico, resultando en la aparición de asma refractaria y muerte súbita.

* Los agonistas adrenérgicos menos selectivos como la adrenalina inhalada y las tabletas de efedrina también han sido usados. Estos medicamentos tienen efectos adversos cardíacos a frecuencias similares o menores que el albuterol. Al ser usados como medicina de alivio sintomático y no de uso prolongado, la adrenalina inhalada ha demostrado ser un agente efectivo en la culminación de una crisis asmática. En situaciones de emergencia, estas drogas se pueden administrar de manera inyectada, aunque dicha práctica ha disminuido por razón de los efectos secundarios.

* Medicamentos anticolinérgicos, tales como el bromuro de ipratropio pueden ser usados y no tienen los efectos cardíacos, de modo que pueden ser administrados en pacientes con cardiopatías, sin embargo, toman aproximadamente una hora para surtir efecto y no son tan poderosos como los agonistas de los receptores adrenérgicos β2.

* Los glucocorticoides inhalados por lo general son considerados medicamentos preventivos, sin embargo, se ha desmostrado el beneficio de 250 µg de beclometasona cuando se toma en una combinación con 100 µg de albuterol

  

La causa del ataque de asma es la estrechez de los finos conductos del aire del pulmón. La estrechez de estos conductos entra en el concepto de las enfermedades alérgicas. Los síntomas principales son la opresión y la angustia, junto con la sensación de ahogo o falta de aire. A pesar de sus apariencias, el asma no es enfermedad peligrosa. Solamente cuando los ataques son muy frecuentes se debilita el corazón y se nota gran decaimiento en las fuerzas corporales.

Causas. La alimentación, pues muchos ataques de asma son debidos a digestiones difíciles, a comidas abundantes y cenas copiosas. Otra causa es el factor nervioso, pues muchas veces se presentan ataques de asma sin más causa que el factor nervioso. Otra causa, el clima; por eso contribuye al alivio del asmático el sólo cambio de clima caliente a frío o al contrario.

Tratamiento. Normalizar la digestión; refrescar el interior del vientre con baños genitales y cataplasma de barro durante la noche. Un procedimiento muy eficaz para abreviar o cortar el ataque de asma es el chorro frío de nuca y espaldas. Combatir las causas que favorecen la aparición de los ataques. Baño vital; baños de sol y de aire. Gimnasia respiratoria. Dos o tres veces por semana baños de vapor de pecho y de cabeza. Baños de pies alternos calientes y fríos. Evitar los resfriados. Dormitorio aireado pero sin corriente. Evitar el humo y el polvo. Abstenerse de fumar. Para el uso de las plantas medicinales.

 

REFLEXIÓN: Vengo de una cepa de características asmaticas por parte de la herencia de mi madre, HOY mi hermana chica se encuentra con grandes crisis asmaticas que le provocan gran dolor, "estreñimiento" tóraxico, y le quita la posibilidad de respirar. Pero esto no es sólo cuestión de herencia, ni de me tocó a mí pues yo tengo que lidiar con esta enfermedad... Qué hay de los índices de contaminación? Cuántos cigarrillos te fumas al día? NO TE CRÍTICO, yo también lo hago y no me justifico en la excusa de que mi mejor amiga es la angustia y la ansiedad,... pero si vieras pabellones en que pequeños son nebulizados, sin duda tu corazón estaría desgarrado al igual que el mío, no es necesario padecer de asma para tener una opresión en el pecho que no te deje respirar, qué tal la pena, un gran problema, imaginate lidiar con un bulto de 15 kls aprox. en tus costillas que oprima tus pulmones y te generé la desesperanza de que te arrebatan la vida... porque somos culpable, la cuenca de santiago nos albergo, pero no con estas cantidades de partículas disueltas de SMOG que hoy no nos dejan ver porque hay una nebulosa ante nuestros ojos que nos oculta la realidad...

 

SMOG I HATE YOU MOTHERFUCKER!

 

Hermana, perdón por contribuir y expeler humo de cigarrillo, sólo lo hago en sociedad, pero daré está charla cada vez que se prenda uno, tendrás segundos de alivios :)

 

Nombre científico: Glycyrrhyza glabra L.

 

Nombre vulgar: : Regaliz, palo dulce, regalicia

 

Familia: Papilionáceas

 

Descripción: Hierba perenne de la familia de las papilionáceas de hasta 1' 5 m de altura. Tallos erectos, glabros, ramificados por la parte inferior. Hojas con peciolo corto, compuestas con hasta 17 foliolos pegajosos. Flores axilares de color azul o violáceo, agrupadas en racimos, con 1 cm, más o menos, de longitud. El fruto es un legumbre de hasta 2 cm de longitud.

 

Hábitat: Procede de la Europa mediterránea y de Asia Menor y se encuentra cultivado en muchos lugares, habiéndose naturalizado en muchos de ellos en lugares húmedos, lechos de ríos secos, barrancos, etc.

  

Principales componentes: :

 

* Azúcares : glicirricina, glucosa y sacarosa

 

* Flavonoides: licoflavonol, licoricona, glycirol, glyzarina, formononetina, isoliquiritigenina, glabrol, glabrona,

 

* Saponinas

 

* Taninos

 

* Betacarotenos

 

* Aminoácidos: asparagina.

 

* Proteínas

 

* Ácidos: salicílico, málico, betulínico, glicirrético

 

* Minerales: Calcio, cromo, cobalto, fósforo , magnesio potasio, silicio y sodio.

 

* Vitaminas: Vitamina C y Tiamina.

       

Partes activas: La raíces

  

Usos medicinales:

 

La regaliz es una planta cuyo usos usos medicinales son muy variados y se esta utilizando mucho actualmente. Tanto su raíz seca en preparaciones caseras como toda una serie de productos normalizados y presentados de diversas maneras

( cápsulas, tabletas, comprimidos, tinturas, crema seca, etc.) puede ser encontrado en las farmacias o herboristerías. Todas ellas tienen como base la raíz de esta planta y su componente principal, la glicirricina. Este componente se ha venido elaborando tradicionalmente a partir de las raíces de tres años que todavía no han producido fruto y que suelen recogerse durante el octubre y el noviembre. El proceso consiste en machacarlas y hacerlas hervir a fuego lento en calderos de cobre removiendo constantemente hasta que se se forme una pasta consistente. A esta pasta se le da la forma oportuna y se deja secar sobre tableros de madera. Actualmente modernas máquinas realizan el proceso en cámaras de vapor.

 

En la composición del regaliz suelen entrar otros productos edulcorantes que disimulan su amargor natural. Como la glicirricina presenta ciertas incompatibilidades y un posible toxicidad, como veremos más tarde, se venden productos normalizados de regaliz sin este componente, que se llaman DGL ( Deglycyrrizinated Licorice , que quiere decir en inglés regaliz sin glicirricina) y que tiene unas propiedades diferentes a la variedad completa.

 

Además de preparados normalizados de regaliz, se utiliza también su raíz seca triturada para realizar decocciones y tinturas realizadas con la raíz seca macerada en alguna bebida alcohólica de 45 º durante 15 días. La ventaja de la raíz es que, una vez recogida y lavada adecuadamente, se puede guardar y se conserva perfectamente hasta que decidamos realizar una preparación.

   

Propiedades medicinales:

 

Usos Industriales:

   

Dado el poder del regaliz como edulcorante, se utiliza habitualmente en la confección de alimentos y bebidas, superando en mucho el poder de otros endulzantes. Igualmente se utiliza en la industria del tabaco para mejorar el sabor de los cigarrillos.

  

Toxicidad: La glicirricina posee propiedades mineralcorticoide y glucocorticoide. Su uso prolongado produce efectos negativos en el organismo con aumento de la presión sanguínea ( hipertensión ) , aumento del sodio y retención del agua. Se produce una perdida anormal de potasio que conduce a un estado llamado hipocalemia o falta de potasio en la sangre.

 

Muchas de las intoxicaciones se producen de una manera inconsciente con el uso habitual de esta planta en caramelos, sobre todo aquellos para refrescar el aliento. Otros causantes de las intoxicaciones son beber cantidades grandes de bebidas que contengan regaliz, como el anisette, el fumar mucho tabaco tratado con esta planta, el comer gomas de mascar o caramelos. La dosis tóxica depende de cada individuo pero la Comisión Europea, en un estudio del 2004, recomienda que las dosis diarias de ácido glicirrético no supere los 100 mg diarios ( Se conoce el caso de una mujer inglesa que había estado comiendo un paquete de 200 gr. diarios de caramelos de regaliz para aliviar el estreñimiento. Al final tuvo que ser ingresada en el hospital por presentar un estado general muy débil con una presión sanguínea muy elevada)

 

En un estudio realizado en Irán se comprobó como la administración de 1,3 gr. de extracto seco de regaliz durante diez días consecutivos disminuía la testosterona de los afectados e inhibía su deseo sexual. Igualmente un estudio llevado a cabo en Finlandia llegó a la conclusión que el consumo de regaliz llevada a partos prematuros.

 

No se puede utilizar en caso de diabetes del tipo II, en pacientes con hipertensión arterial, con aquellos que tengan poco potasio en la sangre, en enfermos de hepatitis y durante el embarazo.

  

Síntomas: Dolor de cabeza por aumento de presión, edemas principalmente en la cara y en los tobillos , sensación de extremidades ardientes, debilidad, calambres, orina de color oscuro, perdida de la menstruación, problemas en la libido por aumento de la testosterona en los hombres, arritmia, etc.

   

El uso de la regaliz esta desaconsejado si se están tomado otros medicamentos como los que se suministran para aumentar la presión arterial ( Pueden provocar un aumento demasiado elevado de la tensión ) , los corticoides ( al igual que la regaliz, producen retención de líquidos) o los productos que se toman para tonificar el corazón.

 

Tratamiento: Abandonar la ingestión de este producto, atención médica en casos necesarios con respiración asistida y vigilancia del ritmo cardíaco. En muchos casos será necesario proporcionar algún hipotensor para bajar la presión arterial y controlar los electrolitos, especialmente el potasio.

   

Wikipedia: "Like most adrenocortical steroids, methylprednisolone is typically used for its anti-inflammatory effects. However, glucocorticoids have a wide range of effects, including changes to metabolism and immune responses. The list of medical conditions for which methlyprednisolone is prescribed is rather long, and is similar to other corticosteroids such as prednisolone. Common uses include arthritis therapy and short-term treatment of bronchial inflammation or acute bronchitis due to various respiratory diseases. It is used both in the treatment of acute periods and long-term management of autoimmune diseases, most notably Systemic lupus erythematosus."

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

Những trải nghiệm trong đời được lưu giữ như thế nào?

 

Những tác động gì gây mất trí nhớ (quên số điện thoại của chính nhà mình hay phản xạ về trí nhớ không còn nhạy bén)... còn nhiều bí ẩn khác mà riêng ngành tâm lý học chưa thể lý giải. Tuổi tác, thiếu ngủ, chất độc hại (thuốc lá, rượu...), chấn thương, bệnh tật đều có thể ảnh hưởng xấu đến trí nhớ, vì thế cần nhận diện đúng những tác động làm suy giảm hay cải thiện năng lực của trí nhớ.

 

Nghiện rượu có hại cho trí nhớ không? Đúng, rượu mạnh, nồng độ cồn cao nếu uống trong thời gian dài (vài năm) gây ra những tổn thương không hồi phục cho tế bào thần kinh. Y học đã chứng minh rằng, những người nghiện rượu có sự biến đổi về trí nhớ lâu dài do tổn thương não.

 

Stress làm cho người ta dễ quên? Khi gặp những stress nghiêm trọng trong đời sống (buồn đau, căng thẳng...) thì có ảnh hưởng xấu đến trí nhớ. Khi đó, cơ thể tiết ra nhiều hormon glucocorticoid của tuyến thượng thận và cuối cùng đã ảnh hưởng đến vùng hải mã của não, một vùng não "giống như nhạc trưởng của hoạt động lưu giữ trí nhớ". Một số bệnh nhân trầm cảm nặng có vùng hải mã bị teo. Những stress nhỏ hàng ngày cũng ảnh hưởng đến trí nhớ gần.

 

tin180.com/wp-content/blogs.dir/12/files/2010/03/Kham-pha...

 

Giấc ngủ cần thiết để duy trì trí nhớ? Ban đêm là thời gian để não sàng lọc và sắp xếp lại những ký ức ban ngày. Chính trong giai đoạn ngủ chính thức mà những tế bào thần kinh sắp xếp lại những thông tin thu nhận được ban ngày. Nếu thiếu ngủ thì việc lưu giữ ký ức sẽ bị rối loạn.

 

Thuốc chống lo âu có thể gây chứng quên? Trong dòng benzodiazepine (valium, temasta...) mỗi loại thuốc có hiệu ứng khác nhau với trí nhớ. Một số có tác động đến lưu giữ những thông tin mới, một số khác đến trí nhớ về ngữ nghĩa hoặc đến trí nhớ hoàn cảnh. Nếu quý ông nào đã quên ngay người phụ nữ đã ngồi trò chuyện vui vẻ và cùng ăn cạnh mình trong bữa tiệc tối hôm trước thì cũng đừng quá lo lắng, tác động đến trí nhớ sẽ hết sau đợt điều trị.

 

Cannabis (1 loại ma tuý) có ảnh hưởng trí nhớ dài lâu? Cannabis có ảnh hưởng đến trí nhớ gần và lúc đầu không gây ra tổn thương. Tác động đến não ngừng khi không sử dụng nữa. Trạng thái phê gây ra những rối loạn trong trí nhớ về những sự việc mới xảy ra và gây ra những tổn hại không hồi phục đến một số loại tế bào thần kinh.

 

Đi máy bay có dẫn đến mất trí nhớ? Theo một số nghiên cứu thì những nhân viên hàng không dễ gặp vấn đề về trí nhớ nhưng có thể chỉ vì thiếu ngủ.

 

Trí nhớ bắt đầu suy giảm từ tuổi 20? Một nghiên cứu ở Mỹ cho rằng, trí nhớ bắt đầu suy giảm khi qua tuổi vị thành niên (tức sau tuổi 20) và có thể trước nữa. Ngược lại, cuộc khảo sát này cũng đã cho thấy rằng vốn từ ngữ và khả năng nói năng trôi chảy lại tăng lên từ tuổi 70.

 

Nghe băng cát-xét trong lúc ngủ có phải là một phương pháp học? Không phải vì nghe băng cát-xét trong lúc ngủ có thể giúp nhớ được bài học. Mà sự đọc và xem lại bài trước buổi thi vấn đáp sẽ giúp cho não "tái hiện" lại những gì đã học tối hôm trước.

 

Sữa đậu nành có phải là thức ăn lý tưởng để tăng cường cho các tế bào thần kinh? Giá trị của sữa đậu nành đến trí nhớ có phần cường điệu bởi vì không có thức ăn màu nhiệm nào cho não. Não cần đến 40 chất gồm 13 loại vitamin, 15 chất khoáng và vi chất, 8 acid amin và 4 chất béo. Tóm lại, cần có một chế độ ăn đa dạng và cân đối mới đảm bảo có chất lượng trí tuệ tốt.

 

Có phải trí nhớ gần của con người có thể lưu giữ được tối đa 15 từ? Trí nhớ gần chỉ có thể lưu giữ tốt không quá 7 từ (cộng trừ 2 tuỳ theo mỗi người) do đó không nên cố nhớ cả một danh sách.

 

Có phải buổi sáng trí nhớ lưu giữ tốt hơn? Từ giữa buổi sáng đến giờ ăn trưa là quãng thời gian có khả năng nhận thức cao nhất. Buổi sáng chắc chắn là lúc tốt nhất để học. Ngược lại, ngay sau bữa ăn trưa, khả năng tập trung chú ý kém đi, nhất là sau bữa ăn thịnh soạn và nhiều mỡ, khi đó còn dễ buồn ngủ.

 

BS. Xuân Anh

 

(theo suckhoedoisong)

(source: tin180.com/suckhoe/?p=9711 )

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

At the Cluny Museum, medieval culture showcases its ancestral knowledge. It took five centuries to discover that the thymus and the genitals are connected, as seen in this statue of the first man to experience desire, through a dream about a mythical serpent.....

Within the thymus, regulation of the cellular crosstalk directing T cell development depends on spatial interactions within specialized niches. To create a spatially defined map of tissue niches guiding human postnatal T cell development, we employed the multidimensional imaging platform co-detection by indexing (CODEX) as well as cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) and assay for transposase accessible chromatin sequencing (ATAC-seq). We generated age-matched 4- to 5-month-old human postnatal thymus datasets for male and female donors, identifying significant sex differences in both T cell and thymus biology. We demonstrate a possible role for JAG ligands in directing thymic-like dendritic cell development, identify important functions of a population of extracellular matrix (ECM)− fibroblasts, and characterize the medullary niches surrounding Hassall’s corpuscles. Together, these data represent an age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and T cell development arise, providing an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.

 

The thymus is the primary organ responsible for the generation and selection of mature, functional, and self-tolerant T cells.1 Effective T cell development is a critical component of our immune system’s ability to accurately and exclusively identify and kill foreign entities such as pathogens. During early postnatal T cell development—the period in life when T cell development is most active2—thymic seeding progenitors migrate to the thymus and mature into thymocytes. Thymic architecture is highly organized to provide spatially defined, stage-specific signaling cues to migrating thymocytes that guide development toward functional mature T cells.3,4,5,6

Recent single-cell sequencing resources demonstrating the diversity of human thymus tissue are incongruous with our current framework of thymus structure and organization,7,8,9,10,11,12,13,14,15,16,17,18,19 which describe a general migratory path thymocytes take through the cortex and medulla during conventional αβT cell development. Spatial transcriptomic sequencing of human thymus has demonstrated a deeper granularity of thymic niches and their evolution during fetal development to support different waves of non-conventional T cells.19,20 However, our understanding of how human postnatal thymus niches support conventional and non-conventional T cell development, T-lineage branching, and alternative lineage development remains limited.3,4,6 T cells generated at this stage of postnatal human development will become the foundation of our immune system, patrolling the body for decades.21 Thus, insights into early postnatal thymus niche biology are crucial to understand how our adaptive immune system is built and how perturbations in postnatal T cell development may emerge as immune dysfunction later in life.

To create a spatially defined map of tissue niches guiding human postnatal T and alternative lineage cell development, we employed multi-dimensional spatial proteomic imaging using co-detection by indexing (CODEX),22,23 single-cell transcriptomic-proteomic profiling using cellular indexing of transcriptomes and epitopes sequencing (CITE-seq),24 and single-cell assay for transposase accessible chromatin sequencing (ATAC-seq).25 Given the emerging recognition of sex differences in thymus gene expression and function,26,27,28,29,30,31 we collected and analyzed samples from male and female donors. Our analysis identifies significant sex differences during early postnatal development that affect T cell and thymus biology through common and cell type-specific mechanisms. Additionally, we highlight key cell types contributing to thymic involution that exhibit sex-based differences in thymic growth and early transition toward adipogenesis. These data suggest that kinetic differences in thymic involution are present between sexes and, importantly, that mechanisms driving thymic involution begin early in life. Altogether, these data represent a powerful age-matched spatial multiomic resource to investigate how sex-based differences in thymus biology and T cell development arise, and how they contribute to sex differences in diseases caused by immune dysfunction.

Results

Spatial multiomic profiling of human postnatal thymus identifies sex-based differences in T cells and thymus biology

We performed single-cell CITE-seq, ATAC-seq, and CODEX imaging on 4–33 months human postnatal thymuses, including 6 (3 female and 3 male) 4- to 5-month-old age-matched samples (Table S1). Each donor sample was processed simultaneously for CODEX imaging and sequencing (Figure 1A). We included a comprehensive 137 antibody panel (Data S1), allowing us to compare epigenomic, transcriptomic, and proteomic expression kinetics across developing thymocytes and enabling direct comparison of cells identified via phenotypic expression in CODEX with cells captured via CITE-seq. Prior to sequencing, we enriched CD45− non-hematopoietic cells and CD25+CD8− regulatory T (Treg) cells to ensure coverage of low-abundance cell types. After quality control and computational merging of individually sequenced patient datasets, we obtained a total of 74,334 cells with CITE-seq, including 19,434 non-T-lineage cells, and captured 25,717 nuclei with ATAC-seq. Importantly, cell proximity in CODEX tissue niches was used to screen predicted receptor-ligand interactions.

 

Figure 1 Spatial multiomic analysis identifies sex-biased characteristics of thymic niches

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CITE-seq cells were clustered based on transcriptional expression and annotated based on marker gene and surface protein expression (Figure S1A; Table S2).7,8 ATAC-seq clusters were computationally labeled using CITE-seq reference cluster labels, which identified 34 ATAC-seq cluster transfer labels for dataset integration (Figures 1B and S1B). We captured 54,900 thymocytes spanning development from early thymic progenitors (ETPs) to mature single positive (SP) T cells, immature innate cells, innate-like cells, and Tregs. We identified three Treg populations expressing canonical lineage markers, namely Treg progenitors (Pro-Tregs), thymic Tregs (tTregs), and recirculating/resident Tregs (rrTregs).32 We also identified antigen-presenting cells, including B cells, mast cells, monocytes, and six populations of dendritic cells (DCs).33 In addition to the activated DCs (aDCs), plasmacytoid DCs (pDCs), DC1, and DC2/3 populations described by Park et al.,7 we found proliferating populations of pDCs and DC1. We also captured 7,093 epithelial cells, including cortical epithelial cells (cTECs), medullary epithelial cells (mTECs), activated mTECs, and mimetic TECs.

Importantly, we captured 7,721 mesenchymal cells, which contribute to negative selection and thymic involution.9,19,34,35,36 Subclustering identifies important mesenchymal cell types, including two populations of endothelial cells (ECs) defined by differential expression of Notch ligands (ECs, ECs (Notch)). Additionally, we identified lymphatic ECs (LECs), pericytes, vascular smooth muscle cells (VSMCs), and five distinct fibroblast cell types, including DPP4+ capsular fibroblasts (DPP4+ capFibs), capsule fibroblasts (capFibs), medullary fibroblasts (mFibs), KRT+ fibroblasts (KRT+ Fibs), and proliferating fibroblasts (Fibs (P)).

We imaged each tissue sample with a custom 48 antibody CODEX panel to study the architecture and function of niches guiding thymocyte development, aiming to define the niche characteristics guiding T-lineage branch points. Stage-specific thymocyte phenotyping markers (CD62L, CCR7, CD1A, CD5, CD7, CD4, CD8, CD3, CD45RO, CD45RA, FOXP3, and SATB1) identified CD3+ double positive cells (DPs) undergoing T-lineage commitment toward CD4 or CD8 T cells. Phenotyping markers for non-T-lineage hematopoietic cells (CD19, CD11c, CD11b, and CD68), epithelial cells (EPCAM and KRT5/8), mural cells (MCAM and SMA), ECs (CD31), and fibroblasts (PDGFRA) identified the remaining major cell types defining thymic niche architecture. Finally, we included functional markers to define patterns of antigen presentation (CD86), human leukocyte antigen (HLA) class I and II expression (HLA-ABC and HLA-DR,DP,DQ), adhesion ligands (ICAM and VCAM), Notch ligands (DLL1, DLL4, JAG1, and JAG2), T cell activation (PD-1), self-tolerance (PD-L1), proliferation (Ki67), and enzymatic regulation (15-PDGH). In sum, our CODEX panel enabled investigation of spatially regulated mechanisms directing human T cell development.

Using neural-network-driven cell segmentation and Leiden-based clustering,23 we identified individual cells within thymic tissue for each sample (Figure S1C). We annotated cell types based on tissue location and phenotypic expression compared with CITE-seq clusters (Figure 1C), performed proximity-based neighborhood clustering to identify niches,23 and annotated niches based on location and cell type composition (Figure 1D; Figure S1D). This analysis quantified proximity-based cell-cell interactions (Figure S1E) and served as a platform to interrogate spatially defined thymic niche biology via integrated sequencing-imaging analysis.

Because of known sex differences in thymus and T cell gene expression,31 we compared our age-matched male and female samples separately. In line with prior reports of sex-biased gene expression on autosomes,37,38,39,40 only 2% of male differentially expressed genes (DEGs) were found on the Y chromosome and 0.3% of female DEGs were found on the X chromosome (Tables S3 and S4). Gene set enrichment analysis (GSEA) on male vs. female cells for each cell type identified pathways commonly upregulated in either sex (Figure 1E; Data S1). Pathways differentially regulated across hematopoietic, epithelial, and stromal cells represent cell-intrinsic sex-based differences. Female cells have higher gene expression of transcription, energy regulation, and antigen presentation. Male cells, by contrast, have increased gene expression of proinflammatory signaling, amino acid metabolism, and G protein-coupled receptors (GPCR) signaling. The top differentially expressed energy regulation and metabolism pathways were similarly sex-biased in human kidney,41 suggesting multiple organs show consistent sex-biased enrichment of pathways linked to metabolism and energy production. Our data align with sex-biased trends identified in human induced pluripotent stem cell (iPSC) lines42 and other human organs,43 indicating these pathways often differ between male and female cells across various cell types.

By contrast, some pathways showed cell type-specific sex-biased enrichment. Female T and hematopoietic cells showed enrichment of interferon signaling, and female fibroblast and perivascular cells were enriched in extracellular matrix (ECM)-centric pathways (Figure 1E). Our dataset also identified differential sex-specific pathway enrichment between cell types. Gene expression indicated higher cytokine signaling in T cells and hematopoietic cells in females and in epithelial and mesenchymal cells in males (Figure 1E). These data show significant gene expression differences in male and female thymic cells. To demonstrate sex differences at the proteomic level, we identified genes with a log fold change greater than 1 that contributed to increased chemokine signaling in male T cells. CXCR4, an important chemokine receptor in thymocyte migration and development, had increased expression in male progenitor T (pro-T) cells, which we confirmed via flow cytometry (3 male, 3 female; p = 0.03; Figure S1F). As higher levels of cytokine and interferon signaling have been previously shown to influence thymus and T cell biology,44,45 our data suggest male and female T cells develop in different signaling environments and may respond differently to cytokine stimuli.

Next, we quantified cell type abundance within male and female tissues, demonstrating differences in cortical and medullary cell distributions between sexes. When normalized to the total number of cells per lobe, female thymus lobes contained significantly more DPs (p = 0.011) and cTECs (p = 0.0023). In males, we found significantly more SPs (p = 4.2 × 10−4), CD3+ DPs (p = 9.9 × 10−4), activated mTECs (p = 0.0014), and VSMCs (p = 2.4 × 10−6) (Figure 1F). Given that thymus lobules with more DPs and cTECs would have a greater proportion of cells undergoing positive selection and lobules with more medullary cells would have more cells undergoing negative selection, these data suggest that sex differences in cell type abundance may influence the resources directed toward specific stages of thymocyte selection. Alternatively, these results may suggest that male and female thymuses are developmentally asynchronous, with males exhibiting faster growth and involution kinetics, resulting in decreased cortical-to-medullary ratios even in early neonatal stages. We focused further analyses on sequential developmental niches, including analysis of sex differences in cell types and niches at each stage.

JAG1 skews ETP development toward thymic DCs

We first analyzed the cortico-medullary junction (CMJ) where cells home to the thymus (Figure 2A). This region recruits and supports ETPs10 and is composed of ECs, VSMCs, and pericytes expressing the Notch ligand JAG1 (Figures 2B and 2C). CITE-seq demonstrated that the cell adhesion molecule used by ETPs to enter the thymus, CD62L, is quickly downregulated upon CMJ entrance through the vasculature (Figure S2A). However, recently immigrated CD62L+ double negative cells are frequently located in the subcapsular zone (Figure S2B), suggesting that ETPs enter the thymus and rapidly migrate to a subcapsular niche where DLL4, a more potent Notch ligand, is highly expressed on fibroblasts and subcapsular epithelial cells (Figures 2D and S2C). However, the concentrated presence of JAG1 at the entry point indicates that ETPs are first exposed to this Notch ligand.

 

Figure 2 Thymic progenitors entering via the corticomedullary junction are exposed to a gradient of Notch ligands, which influence lineage specification

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CellChat46 pathway analysis showed that JAG1-NOTCH1 interactions between endothelial and perivascular cells are enriched with ETPs (Figure 2E), while JAG1-NOTCH2 and JAG1-NOTCH3 interactions are enriched with DC1, DC1 (P), DC2/3, and aDCs (Figures 2E–2G). These data suggest that JAG1 could induce commitment toward other hematopoietic lineages, such as pDCs, conventional DCs (cDCs), or macrophages, which are known to develop within the thymus.10 As JAG ligands induce weaker Notch induction,47,48,49,50 we hypothesized that early contact with ETPs could maintain T-lineage potential while cells migrate toward DLL4 in the subcapsular niche.

We first analyzed the ability of the four thymic Notch ligands to induce T-lineage commitment or alternative lineage development from cord-blood-derived CD34+ hematopoietic stem and progenitor cells (HSPCs) in a defined, feeder-free culture system44 (Figure 2H). We included titrated concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced by mast cells at the CMJ, to support DC development.51 We found that only DLL1 and DLL4 ligands induce T-lineage commitment, whereas JAG ligands or no ligand controls supported myeloid cell development and did not induce T-lineage commitment (Figure S2D). Specifically, JAG ligands with GM-CSF skewed CD68+ DC development toward CD14− DC1 cells, while no ligand controls skewed CD68+ DC development toward CD14+ DC2/3 cells (Figures 2I and S2E).

Next, to test our hypothesis that Notch signals via JAG1 ligands could act as a bridge toward later DLL4 interactions, we analyzed cells grown on JAG1 for 3, 5, or 7 days prior to DLL4 transfer (Figure 2J). We found that cells cultured on JAG ligands or no ligands for 3 days maintained reduced T-lineage commitment compared with DLL1 or DLL4 cells (pJAG1 = 0.033; pJAG2 = 0.017), whereas cells cultured on JAG ligands for longer than 3 days lost T-lineage potential (Figure 2K), indicating that JAG ligands could not support T-lineage potential.

We next analyzed the contribution of different Notch ligands to the development of male and female ETPs (Figures S2F and S2G). Our data suggest that JAG ligand interactions are more abundant and diverse in females, with JAG1-NOTCH1 interactions enriched in female ETPs and DLL4 interactions enriched in male ETPs.

Together, these data suggest that timely migration from the CMJ to DLL4 ligands at the subcapsular zone is critical for T-lineage commitment, and exposure to JAG ligands at the CMJ can guide alternative lineage development toward thymic-derived DCs. Our data further demonstrate previously unrecognized sex-biased regulation by Notch ligands.

Analysis of the subcapsular zone identifies sex-based differences in fibroblast regulation of DP development and thymus growth

From the CMJ, ETPs migrate to the subcapsular zone via a CCL25-CCR9 chemokine gradient established by cTECs and directed to pro-T, DP (P), and DP2 (Q), but not DP1 (Q) cells (Figure 3A; Figure S3A). The subcapsular niche consists of JAG1+ VCAM1+ DCs, cTECs, capsular fibroblasts, DPP4+ capsular fibroblasts, and proliferating fibroblasts, which secrete and maintain spatially regulated ECM ligands to support sequential thymocyte development (Figures 3B and 3C; Figure S3B and S3C).

 

Figure 3 Fibroblasts in the subcapsular zone contribute to regulation of thymus biology and T cell progenitor development

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GSEA showed that DPP4+ capsule fibroblasts were enriched in HSP90 chaperone cycle for steroid hormone receptors (padjusted = 0.0065; 18/52 pathway genes significantly upregulated) (Data S1), suggesting an enhanced response to steroid hormones and supporting their role in sex hormone-based thymic involution.9 By contrast, capFibs were enriched for genes related to cytokine (interleukin [IL]-33, padjusted = 1.50 × 10−6; IL-34, padjusted = 3.56 × 10−7) and chemokine signaling (CCL2, padjusted = 5.10 × 10−40; CXCL3, padjusted = 0.020; CXCL12, padjusted = 1.78 × 10−8; CXCL14, padjusted = 3.63 × 10−15), functions previously attributed to TECs. Furthermore, CellChat identified cortical fibroblasts as major contributors to insulin growth factor (IGF) signaling through predicted signaling to cTECs, which are found in close proximity in the cortex (Figure S3D), via IGF2-IGF1R and IGF1-IGF1R axes, and to ETPs and β-selection cells, which were found under the capsule (Figure S2B), via an IGF2-IGF2R axis (Figures 3D–3F).

We next explored the role of proliferating fibroblasts. GSEA comparisons between capFibs and Fibs (P) showed marked differences in signal transduction pathways. CapFibs resembled traditional fibroblasts, which upregulate tyrosine kinase, angiogenesis, and ECM regulation and deposition pathways, whereas Fib (P) upregulates WNT signaling and cell sensing pathways, including genes involved in transient receptor potential (TRP) channels in the stimuli sensing channels pathway and taste receptors (TASRs) (Figure 3G; Data S1). Interestingly, CODEX images identified ECM− PDGFRa+ fibroblasts lacking extra domain A fibronectin (EDA-FN) expression, indicating that Fibs (P) are not involved in fibrotic matrix deposition unlike capFibs (Figure 3H; Figure S3B). Fibs (P) form a network of PDGFRa+ cells throughout the cortex that does not overlap with the cTEC network, yet maintain cell-cell contact in specific niches and often localize near cortical capillaries (Figure S3D).

We found sex-specific differences in vascular endothelial growth factor A (VEGFA) signaling within ECM− fibroblasts (Fib (P)) and other mesenchymal cells. Although all thymic fibroblasts produce the angiogenesis growth factor VEGFA, male fibroblasts express more than female cells (Fibs (P): padjusted = 0.0306; DPP4+ capFibs: padjusted = 0.0318; mFibs: padjusted = 1.85 × 10−6) (Figure 3I). Given that postnatal male thymuses are larger than female thymuses in humans and primates26 (Figure S3E), male fibroblasts may provide increased VEGFA to support angiogenesis and rapid thymic growth observed during postnatal development.52 Additionally, male mFibs have higher expression of FGF7 (padjusted = 0.0154), which regulates thymus size.53 CellChat predicts that male Fibs (P) are enriched in FGF10 compared with females, which supports cTEC proliferation and vascular growth,53,54 and only male VSMCs express FGF18 (Figures S3F–S3H). These sex biases in fibroblast growth factor (FGF) gene expression may contribute to the larger size of early postnatal male thymuses by stimulating epithelial and EC growth and proliferation.

Comparison of DEGs between male and female mesenchymal cells found increased expression of adipogenesis, cytokine, and GPCR signaling pathways in DPP4+ capFibs (Figure 3J). We also found increased expression of APOD, a gene associated with androgen, estrogen, progesterone, and glucocorticoid signaling,55,56 across male fibroblast populations (Fibs (P): padjusted = 2.18 × 10−26, mFibs: padjusted = 8.45 × 10−32) (Figure S3I). Given the association of hormone signaling with thymic involution,29,52,57 these findings suggest early initiation of thymic involution in postnatal males.

In sum, we identified three roles for fibroblasts within the subcapsular niche: maintaining tissue structure and organization via ECM and chemokine signaling, directly regulating cTEC maintenance and expansion, and potentially coordinating T cell development directly through growth factors and cell-cell interactions.

Human postnatal thymocytes may self-select in the cortex to support positive selection of conventional αβT cells

Upon exiting the subcapsular zone, DPs migrate into the inner cortex toward the medulla, where they receive positive selection signals that guide T-lineage branching toward CD4 or CD8 SP cells (Figure 4A). For DPs to transition toward the CD4 lineage, cells must receive T cell receptor (TCR) stimulation through HLA class II interactions, yet previous mouse studies have shown transcriptional downregulation of HLA class I and II in DPs.58,59 Low transcriptional expression is hypothesized to prevent thymocyte-thymocyte self-selection during positive selection, necessitating DP interactions with cTECs to receive positive selection signals.

 

Figure 4 HLA class I and II interactions may support thymocyte positive selection in the inner cortical zone

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Analogous to mouse literature, quiescent human DPs do not express HLA class II transcripts and have closed CIITA promoters (Figures 4B and 4C). Despite the lack of class II mRNA, thymocytes express low levels of HLA class II protein throughout development (Figure 4B). Additionally, in contrast to mouse data, we observe constitutive class I mRNA expression, which increased as cells transitioned toward SPs (Figure 4D). This is consistent with ATAC-seq data demonstrating that the B2M promoter is open throughout thymocyte development (Figure 4E). We confirmed HLA expression via flow cytometry and found that approximately 25% of DPs express both class I and II, and over 65% of DPs are class I+ (Figure S4A). Thus, thymocyte self-selection within the cortex could support positive selection. In support of this notion, CODEX enabled us to identify locations within the cortex devoid of epithelial, fibroblast, endothelial, or DCs but packed with DPs expressing class II+ molecules concentrated at cell junctions (Figure 4F). We confirmed the absence of spindle-like cTEC projections in this niche via confocal imaging (Figure 4G). Additionally, we quantified cell-cell interactions and identified a niche (positive selection niche 1) consisting of class II+ DPs and CD3+ DPs and a niche (self-selection niche) containing mainly class II+ DPs (Figure 1D). Finally, we sorted thymocytes to isolate immature DPs (CD4+CD8+CD3−TCR−) and mature DPs (CD4+CD8+CD3+TCR+) from three donors and cultured them for 7 days in a feeder-free assay. In the absence of epithelial cells, both immature and mature DPs upregulate HLA class II proteins (Figure 4H), and immature DPs continue to mature along their developmental pathway, as indicated by increased percentage of CD27+ DPs in culture after 7 days (Figure 4I).

Next, we identified a niche that directs T-lineage commitment toward CD4 or CD8SPs. We performed differential gene expression analysis on clusters representing this lineage branch point to identify markers for our CODEX panel (Figure S4B). We found SATB1 expression increased as DPs transitioned toward SPs (Figure S4C), and compared with CD8SP transition cells, CD4SP transition cells had higher expression of this master transcription factor60 (Figures S4D and S4E). Imaging analysis confirmed increased SATB1 expression coincides with CD3 upregulation, consistent with a role in late DP development and lineage branching (Figure 4J).7 Neighborhood analysis identified a niche enriched for mature CD3+ DPs in the inner cortex, suggesting that there either exists a niche specifically for late DP development and CD4 lineage transition or that cells are pre-disposed to CD4 lineage development through their TCR and migrate as clonal populations after proliferation at the outer cortex.

We compared cortical niche organization between sexes and found differences in niche organization supporting conventional T cell development, self-selection, and cross presentation. Females showed increased neighborhood interactions between the cortical DC niche containing JAG1+ VCAM+ DCs and the mature DP niche containing CD3+ DPs, the positive selection niche 1 containing class II+ DP cells and CD3+ DP cells, and the positive selection niche 3 containing DCs and DPs (Figure S4F) as well as increased cell-cell interactions between cTECs and class II+ DPs (Figures S4G and S4H). Conversely, males had increased cell-cell interactions between cTECs and CD3+ DPs (Figures S4G and S4H). These data suggest that the proportionally larger female cortex could increase cross presentation from DCs and cTECs to class II+ DPs, possibly facilitating greater use of self-selection as an alternative mechanism for positive selection.

Taken together, spatial multiomic analysis of the inner cortex identified cortical niches supporting specific stages of DP development, including three positive selection niches, a specialized niche for self-selection, and a mature DP niche thymocytes migrate through prior to entering the medulla.

Spatial multiomics identifies key mechanisms regulating negative selection niches in the medulla

Mature DPs enter the medulla, an environment specialized for negative selection, and transition toward CD4 or CD8 lineages (Figure 5A). Within the medulla, cells specialized for negative selection localize around keratinized structures called Hassall’s corpuscles (HCs).61 HCs appear during late prenatal development and are abundant in human postnatal thymuses but rare in mice.62 Here, we demonstrate that HCs can be divided into three major components: an external epithelial border of highly keratinized cells, an inner border of cells expressing prostaglandin-degrading enzyme 15-PGDH (HPGD), and a central PDGFRa+ mass (Figure 5B). HCs produce thymic stromal lymphopoietin (TSLP),61 an analog of IL-7, which activates DCs to increase expression of class II and co-stimulatory molecules CD80 and CD86. Importantly, subclustering stromal populations identified a population of KRT+ fibroblasts resembling cells undergoing epithelial-to-mesenchymal transition (EMT)63 (Figures S5A and S5B). CITE-seq identified TSLP and 15-PGDH mRNA expression in KRT+ Fibs, mFibs, mTECs, activated mTECs, and aDCs (Figure 5C), implicating these cell types as potential contributors to the function of HCs. Finally, given the inner layer of 15-PGDH+ cells, we explored the role of prostaglandin signaling regulation within the medulla. We found that DC1 cells express high levels of PGE2, whereas DC2/3 cells and monocytes express the PTGER2 and PTGER4 receptors, and aDCs express the PTGER3 receptor (Figure 5C), suggesting prostaglandin signaling is a major regulator of DC activity near HCs.

 

Figure 5 HCs represent scalable organizing centers for negative selection in the neonatal thymic medulla

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CODEX imaging suggests HCs act as sub-medullary organizational centers to segregate the inner medulla into specialized niches for negative selection. CD86+ APCs, a subset of which express the co-stimulatory ligand CD40, localize near HCs and in direct contact with CD45RA+ mature SPs (Figure 5D; Figure S5C). In addition, approximately 30% of medullary area is composed of CD19+ B cells,64 which cluster into niches surrounding HCs (Figure S5D). These B cells are found in close contact with—and are often enveloped within—mTECs, potentially facilitating cross presentation with epithelial cells (Figure 5E). These results suggest thymic B cells may comprise an important source of antigen presentation for negative selection.64,65 We quantified medullary neighborhoods and identified six niches, including an mTEC maturation niche, a cross-presentation niche, and four niches specialized for negative selection, which vary in relative location to HCs or the CMJ, as well as their composition of APCs, epithelial, and T cells (Figure 1D; Figure S1D).

Negative selection niches surrounding HCs play a key role in conventional T cell and tTreg development.61 We enriched CD25+ cells for sequencing and found a population of CD25hi pro-Tregs expressing canonical Treg markers CTLA-4, TNFRSF1B (TNFR2), and TNFRSF4 (OX40); positive/negative selection markers (ITM2A, RANBP1, NCL, NME1, MIF, and ATP5G1); Treg developmental long non-coding RNA (MIR155HG)66,67,68,69; and other markers described in mice (Figure S5E). Whereas pro-Tregs expressed high levels of pro-apoptotic gene BCL2L11, mature tTreg subsets expressed the anti-apoptotic gene BCL2. Gene network reconstruction via SCENIC70 identified transcription factor networks activated during pro-Treg to tTreg transition (Figure 5F).

The thymus also contains mature, highly activated Tregs, labeled as rrTregs, believed to have recirculated from the periphery.71,72 rrTregs lack expression of CCR7 or thymic egress markers (KLF2 and S1PR1) but express IL1R2 (Figure S5F), which sequesters the inflammatory cytokine IL-1β to reduce local concentrations.73 CODEX imaging identified tTregs and rrTregs dispersed throughout the medulla, with rrTregs primarily adjacent to CD68+ DCs (Figure 5G). CellChat supported the potential of rrTregs to sequester inflammatory cytokines through interactions with DC2/3 via an IL-1β-IL-1R2 axis (Figure S5G). rrTregs also exhibited a tissue resident Treg phenotype (BATFhigh CCR8+) associated with wound healing and tissue regeneration function,74 and expressed remodeling and tissue repair-related genes such as matrix metalloproteinase enzymes (MMP25 and ADAM19) (Figure S5H). Overall, these findings illustrate Treg diversity in the thymus with their developmental trajectories and functions yet to be elucidated.

Comparisons of male and female rrTregs showed that male rrTregs had higher expression of IL-4 and IL-13, heat shock factor protein 1 (HSF1), and IL-1 signaling pathways (Figure 5H), suggesting rrTreg-mediated regulation of IL-1R2-mediated anti-inflammatory feedback checkpoints is a more prominent mechanism in male tTreg development in early postnatal thymus. Notably, male-activated mTECs have higher expression of CD40 and tumor necrosis factor (TNF) inflammatory pathways than females, possibly resulting in higher rrTreg activity (Figure S5I).

Finally, as Tregs have been shown in mouse to contribute to thymic involution through JAG1,75 we explored sex-based differences in tTreg gene expression. GSEA showed male rrTregs and tTregs have higher expression of adipogenesis pathways (Figures 5H and 5I). Given the presence of cells undergoing EMT, our data underlie the aggressive timeline of thymic involution and suggest that sex-based differences in thymus functional decline begin early in life.

Our detailed examination of the medulla identifies several niches specialized for negative selection, cross presentation, and mTEC maturation around HCs and demonstrates sex biases in inflammatory pathways and thymic involution kinetics within these niches.

Discussion

We performed spatial multiomics to construct a tissue atlas of niches guiding T cell development in early human postnatal thymus. These datasets characterize how key developmental niches drive lineage branch decisions, identify a possible mechanism for conventional αβT cell development through self-selection, and suggest additional functions for mesenchymal cell types governing thymus biology. Furthermore, we discovered several sex-specific differences in thymus cell and niche biology. As T cell development is a dynamic migratory process, knowledge of cell position in combination with proteomic, transcriptomic, and epigenomic sequencing data provides an invaluable resource to predict niche-specific signaling cues directing T cell development, and mechanisms responsible for maintaining tissue structure and directing thymic involution.

We describe an approach to sequencing analysis using multidimensional imaging to establish benchmarks for the location, ligand expression, and composition of key niches in T cell development. This enables us to analyze cell-cell interactions guided by niche composition, identifying physiologically relevant ligand-receptor interactions based on cell proximity within the tissue. Ultimately, this approach maps epigenomic, transcriptomic, and proteomic data to distinct tissue niches at single-cell resolution. Furthermore, we included equal numbers of male and female age-matched thymus samples, enabling comparison between sexes across platform modalities. Our analysis of sex-matched human early postnatal thymus demonstrates the highly plastic nature of thymus lobule organization and resource dedication. Each niche responds to sex-biased developmental kinetics, supporting robust T cell development to ultimately produce functional immune systems in different manners (Figure 6). The findings herein describe only a subset of the data, and we encourage the community to capitalize on this resource to provide further insight into sex differences and targeted niche-specific inquiries.

 

Figure 6 The human early postnatal thymus lobule is spatially organized into sex-biased niches to support stage-specific T cell development

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In our analysis of Notch ligands, we complemented our in silico approach with in vitro analysis. Our analysis suggests that JAG1 at the CMJ cannot support T-lineage commitment as cells migrate toward the subcapsular zone but instead skew alternative lineage development toward a CD14− DC1 subset (Figure 6). CD14 expression on DCs is linked with increased inflammatory cytokine production,76 suggesting that JAG ligands promote non-inflammatory DC phenotypes. These results highlight the importance of precise Notch signaling strength and timing in the thymus and emphasize the need for strict spatial control of different Notch ligands within thymic niches. Our observation of high JAG1 expression in the medulla and decreased DLL4 expression on cTECs outside the subcapsular zone aligns with previous studies on human postnatal thymus.77

In the subcapsular zone, we characterize the important roles of specialized fibroblasts. DPP4+ capFibs, described in mouse as cells with progenitor and anti-fibrotic potential,78,79,80,81,82 are observed as a fibroblast subset responsive to changes in systemic hormone levels. Since thymic function and involution are regulated by sex hormone levels,57,83,84,85 DPP4+ capFibs likely control these processes and are potential targets for addressing age-related thymic involution.86 Previously, only medullary fibroblasts were linked to thymocyte development and selection in the medulla.82 We demonstrate that capFibs may directly support thymocyte development in the cortex by producing growth factors like IGF2 (Figure 6). Blocking IGF2 signaling arrests thymocytes at the double negative stage,87 and our data identify capFibs as the IGF2 source, suggesting capFibs as an additional cell source of cytokines and growth factors for in vitro developmental systems. Finally, we demonstrate that ECM profiles of thymic fibroblasts are tightly regulated based on spatial localization. Future work should characterize how tissue stiffness changes as thymocytes migrate through developmental thymic niches to improve biomaterial strategies for in vitro T cell development.88

Furthermore, we identify a population of ECM− cortical fibroblasts that are enriched in cell sensing pathways, such as TASRs and TRP channels. Interestingly, TASRs regulate cell responses to local soluble substances, such as glucose, modulating release of hormones and other signaling molecules.89 Similarly, TRP channels play roles in cell sensing, such as pheromone signaling, nociception, temperature sensation, and osmoregulation.90 Given the proximity of these cells to vasculature in the cortex, Fibs (P) may play a critical role as regulatory cells by sensing environmental changes and modulating thymus size (Figure 6). Their lack of ECM production and network-like structure resemble fibroblast reticular cells (FRCs) in the lymph node, which rapidly proliferate and remodel the cortex during infection.91 Our data are generated from early postnatal thymus samples, an age with active T cell development, suggesting these fibroblasts expand the thymic cortex similarly to FRCs during infection, signaling through FGF and IGF to stromal and epithelial cells to orchestrate remodeling.

While the dogma in thymocyte positive selection suggests that DPs downregulate class II RNA to prevent self-selection and force interactions with cTECs,58,59 several studies suggest that T-lineage cells can select off each other to support CD4 T cell development.20,92,93,94 Here, we describe an inner cortical niche where class II+ DPs reside that may support positive selection via DP-DP self-selection (Figure 6). We show that immature DPs cultured without epithelial cells upregulate HLA class II and continue to mature and receive positive selection signals. Additionally, upregulated SATB1 expression identifies mature DPs in an inner cortical niche and the CD4 branch of their progeny, suggesting it may determine early lineage specificity. Future work should investigate critical features of this niche and SATB1’s role in thymocyte development.

Within the medulla, we identified a niche adjacent to HCs specialized for negative selection and highlighted the role of rrTregs in modulating the medullary inflammatory environment (Figure 6). The abundance of HCs in human but not mouse, and their proximity to negative selection niches, suggests these structures evolved to provide niche-level organization within the larger human medulla or to regulate negative selection more stringently in longer-lived species.

Comparing male and female tissue showed sex differences in both T cell and thymus biology. Studies on post-pubertal males and females show that sex hormones differentially regulate thymic involution between sexes,26,27,28,29,30,52,57,84,86 and that androgen blockers increase FOXN1 expression, thymic involution, and increased rejuvenation.29,30,52,84,86 Additionally, older males produce fewer recent thymic emigrants and have smaller thymuses compared with females.26,28 Some studies describe decreased numbers of AIRE+ mTECs with age and in females,95 potentially predisposing females who maintain greater thymic function later in life to autoimmune disease.29 These studies also observe less interlobular fat in young female thymus,26 suggesting differences in thymic involution kinetics begin pre-puberty. However, current literature has not addressed transcript-level sex differences underlying functional differences in thymic and immune function. Our analysis uncovers that female thymic cells upregulate energy regulation, transcription, and antigen-presentation pathways, whereas male cells increase proinflammatory signaling, amino acid metabolism, and GPCR signaling. These cell metabolic differences align with transcript-level sex differences in other organs41,42,43 and highlight the need for sex-based cell culture optimization in in vitro T cell culture systems.

In addition to changes common to other organs,40,41 we identify thymus-specific differences affecting key processes in thymocyte development and training. Females have a larger proportion of cortical cells per lobule, aligning with lower thymic involution rates and a larger cortex/medulla ratio.26,27,52 ETPs have enriched interactions with JAG1 as they migrate away from the CMJ, suggesting increased JAG1 interactions could skew ETP lineage commitment toward less inflammatory DC phenotypes (Figure 6). In the female cortex, we observe increased cTEC and class II+ DP interactions and increased interactions between cortical DC and positive selection niches, suggesting thymocyte self-selection may play a larger role during positive selection (Figure 6). Conversely, the female medulla shows decreased inflammatory pathway activation and fewer medullary cells. These data suggest females prioritize generating a larger repertoire of DPs over deleting autoreactive cells through negative selection, potentially contributing to sex differences in autoimmune disease prevalence in females.96

In males, we observe enriched DLL4 interactions with ETPs, which aligns with previous data demonstrating that androgen levels positively correlate with DLL4 on cTECs.29 The male cortex shows increased interactions with mature CD3+ DPs and cTECs, suggesting male thymocytes may have lower proliferation rates post β-selection, allowing sufficient space for positive selection. In the medulla, male-activated mTECs exhibit increased inflammatory pathway markers, and male Tregs exhibit higher inflammatory modulation and activate thymic involution pathways.75 Upregulation of inflammatory modulation by male rrTregs may regulate the higher proinflammatory signaling in male cells (Figure 6). Interestingly, post-pubertal males have more Tregs and fewer CD4 T cells than females, possibly due to a more inflammatory medullary environment skewing CD4 development toward the Treg lineage.31

We further explore sex differences in thymus size control mechanisms. Among fibroblast populations, we find significant differences in expression of growth and angiogenesis factors, such as VEGFA and FGFs, potentially contributing to the size difference in male and female thymuses at this age (Figure 6). These data align with and extend known sex differences in growth factor expression, including sex-biased expression of growth hormone and IGF-1 in regulating size of different tissues.97,98 Importantly, these results indicate sex-specific differences in early thymus structure maintenance and growth, which could skew T cell development. We also establish an early transition toward an adipogenic environment in males. These observations align with findings in model organisms, where young male rats exhibit higher rates of thymic involution52 and early postnatal male primates have a larger interlobular fat area.26 Together, these factors define two possible mechanisms contributing to a male-female difference in thymus size and involution kinetics.

Future studies should test how sex differences at the transcript, niche, and organ level impact differential T cell production and quality as well as explore how sex differences in other organs contribute to known differences in immune responses. Defined in vitro and organoid culture systems replicating the thymic microenvironment present powerful platforms to test if the cell type-specific and sex-specific differences identified here lead to increased autoimmune disease incidence among females and increased infection susceptibility in males. Furthermore, given the surprising sex-based differences at this early postnatal stage, future work should examine aged thymus to investigate how cellular level differences in thymic involution kinetics may translate to larger impacts on our immune system later in life.

Limitations of the study

Our analysis of intra-sex variation is limited by access to patient samples as well as the inability to conduct mechanistic experiments in the context of a whole organism. There is an opportunity for future work to further validate and expand on predicted ligand-receptor interactions.

 

The thymic epithelium is responsible for the secretion of thymic peptides, which intervene in some steps of intra- and extrathymic T cell differentiation. Recent data suggest that thymic hormone secretion is modulated by the neuroendocrine network, comprising thyroid, adrenals, and gonads. However, the role of the pituitary gland in this regulation is still poorly understood. In the present paper we studied the in vivo and in vitro influences of PRL on the secretion of thymulin, one of the chemically defined thymic hormones, by thymic epithelial cells (TEC). When injected daily (20-100 micrograms/20 g) in young or old C57BL/6 mice, PRL induced a specific increase in thymulin synthesis and secretion, respectively, measured by the number of thymulin-producing cells in the thymus and the peripheral levels of the hormone. This stimulation was dose dependent and reversible after the end of treatment. Similar findings have been made in animals with pituitary dwarfism, known to have low levels of circulating thymulin. This stimulatory effect was also observed in primary cultures of human and mouse TEC when PRL (10(-7) to 10(-8) M) was applied to culture supernatants, thus suggesting that PRL could act directly on TEC. In addition, we induced in vivo experimental hypoprolactinemia, treating mice with bromocriptine, a dopamine receptor agonist that inhibits pituitary PRL secretion. Bromocriptine treatment (100-200 micrograms/20 g) yielded a significant decrease in thymulin secretion that could be reversed by coincident treatment with PRL. In the light of previous observations that bovine GH can also increase thymulin production in aged dogs, we performed a series of experiments in vitro to evaluate whether GH has a direct effect on TEC. We observed that only human GH preparations that are known to have a PRL-like effect were efficient in stimulating thymulin biosynthesis and release into the culture supernatants. The effects of PRL on TEC were not restricted to thymic hormone production. We observed that TEC proliferation, as well as the numbers of a TEC subset defined by the expression of cytokeratins 3 and 10, could also be increased by PRL treatment. All these findings show that the pituitary gland directly affects TEC in terms of cytoskeletal and secretory protein expression as well as cell cycle.. This paper reviews the mechanism of sex hormone actions on the thymus, presenting mainly our data obtained at the cellular and molecular levels. First, data supporting the "genomic" action via the nuclear sex hormone receptor complexes are as follows: 1) sex hormone receptors and the thymic factor (thymulin) are co-localized in thymic epithelial cells, but not in T cells; 2) production/expression of thymic factors (thymulin, thymosin alpha 1) are remarkably inhibited by sex hormone treatment; 3) sex hormones cause changes in T cell subpopulations in the thymus; and 4) sex hormones strongly influence the development of thymus tumors in spontaneous thymoma BUF/Mna rats through their receptor within the tumor cells. Secondly, data indicating the "non-genomic" action of sex hormones via a membrane signal-generating mechanism are as follows: 1) the proliferation/maturation of thymic epithelial cells is mediated through protein kinase C activity introduced by sex hormones; 2) sex hormones directly influence DNA synthesis and cdc2 kinase (cell cycle-promoting factor) activity..

pubmed.ncbi.nlm.nih.gov/2737149/

 

www.cell.com/developmental-cell/fulltext/S1534-5807(24)00539-2

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

Annular elastolytic giant cell granuloma is a rare entity, mainly involves sun exposed area with clinical similarity to granuloma annulare, but completely different under microscope, characterized by total absence of elastic fibers in the areas affected, lack of mucin deposition seen in granuloma annulare, and recalcitrant to various treatment modalities. This mid age gentleman was lucky that he responded well to systemic low-dose methotrexate plus glucocorticoid.

More and more successful clinical cases have shown that stem cells have good effects on immune regulation and tissue repair. Many patients with autoimmune diseases from all over the world choose to come to SQ1 medical center for stem cell therapy and had significant improvements.

 

The Beneficial Effects Of Stem Cell Therapy On Autoimmune Diseases

The advantage of stem cell therapy for autoimmune disease is that it can help repair and regenerate tissues that were damaged during the autoimmune attacks, including damaged nerves, skin, blood vessels, organs, etc. At the same time, stem cells can regulate the immune system so that it stops attacking the body. Scientific studies have shown that stem cells can minimize the pathological effects of the immune system self-attacks, thereby avoiding autoimmunity, while maintaining the body’s ability to defend agist foreign substances and real pathogens.

 

Stem cell therapy helps:

Prevent disability and improve patients’ quality of life

 

Inhibit the formation of auto-immune antibodies

 

Alleviate the fibrosis process of damaged organs

 

Helps restore the normal function of damaged organs

 

Normalize immune system function

 

Reduce or eliminate inflammation

 

Alleviate joint pain

 

Reduce medication dosage

 

Reduce recurrence rate

 

Autoimmune Diseases That Stem Cell Therapy Can Treat

 

Lupus erythematosus: including cutaneous and systemic lupus erythematosus

 

Rheumatoid arthritis

 

Sjogren’s syndrome

 

Vasculitis

 

Dermatomyositis

 

Psoriasis

 

Ankylosing spondylitis

 

Ulcerative colitis

 

Hyperthyroidism

 

Crohn's disease

 

Scleroderma

 

Autoimmune thyroiditis

 

Studies have found that stem cells have immunoregulatory functions on various immune cells in the body. According to the follow-ups of our patients, over 76% of the patients had significant relief of symptoms within one year after receiving treatment, and the recurrence rate was significantly reduced. Stem cell therapy has become a wise choice for patients with autoimmune diseases.

 

Learn More About Autoimmune Diseases

 

Autoimmune diseases are diseases in which the body’s immune system malfunctions and causes the body to attack its normal tissues. The immune system is the security system of the human body. Through the immune surveillance mechanism, it always watches over for any pathogen invasion or cell mutations throughout the body. Once an abnormality is found, the corresponding immune response program will be activated to eliminate and remove pathogens or diseased cells.

If the patient’s immune system is over-activated under the combination of genetic defects and predisposing factors, it may mistakenly attack its normal tissues and cells, resulting in organ and tissue damage in the body that leads to autoimmune diseases. Up till now, about 7.6-9.4% of the world’s population suffer from various types of autoimmune diseases. Generally, it is difficult to cure it after the onset of the disease. Most patients need long-term or even life-long medication.

 

Risk Factors For Autoimmune Diseases

 

FactorFactor Description

Family inheritanceIf there are confirmed autoimmune patients with family members, the risk of the disease will increase significantly, such as rheumatoid arthritis, Idiopathic Inflammatory myopathy.

During embryonic development, due to gene mutation, the related immune regulatory system became malfunctions. Genetic mutations lead to susceptible genotypes that will increase the risk of developing autoimmune diseases in patients.

Congenital heart defectCongenital vascular structural defects. these defects could lead to local vascular stenosis.

Autoimmune disease: Malfunction of the immune system, which will attach and damage own tissues and organs.

Infection or disease factorsInfections of various bacteria, fungi, parasites, and viruses, such as streptococcus or Epstein-Barr virus

Abnormal fluctuations of hormone levels in the body

Drugs or other toxic substancesToxic side effects are caused by drug intake, such as antibiotics.

Exposure to certain toxic substances: Such as chemical ingredients, organic solvents, etc.

Lifestyle factorsLong-term smoking (including cigars and pipes) and alcoholism

Long-term sun or UV exposure

Residence in areas with severe air pollution

Long-term exposure to intensive pressure or severe mental stimulation

 

Clinical Symptoms Of Autoimmune Diseases

 

Autoimmune diseases are mainly caused by the dysfunction of the autoimmune system and attack to own tissues and organs. The clinical manifestation of different types of patients are complicated and overlap with each other. However, due to individual differences in the specific damage site and severity, they will present different clinical characteristics.

 

DiseaseCommon Symptoms

Joint bonesPersistent, polyarthritis of the affected joints

Pain, stiffness, swelling, and limited mobility in joints and bones

Stiffness in and around the joints after waking up in the morning called "morning stiffness “

Severe damage to articular cartilage and bone in severely affected patients, leading to joint deformity and loss of function, and ultimately disability

Skin and mucous membranesObvious rash and erythema on the skin, and may aggravate after exposure to light

Mucosal ulceration may occur in some patients, which recurs even if it could heal spontaneously

Dry mouth and eyes

Long-term and repeated skin damage may cause scarring and sclerosis of the skin tissue

Abnormal sensations on the skin surface (such as touch, temperature, etc.), unable to accurately perceive external stimuli and changes

Muscle and soft tissueMuscles and soft tissues are damaged by chronic inflammation, causing redness, pain, and weakness

As the disease progresses, the muscles and soft tissues could be severely damaged, which can lead to muscle wasting and joint deformation.

The central neural system cannot effectively control the movement of muscles in the affected area, especially difficult to perform fine movements.

Patients may also have systemic multiorgan structuralWeakness, fatigue, fever

Anemia, leukopenia, thrombocytopenia

Gastrointestinal discomfort, loss of appetite, and severe cases may be accompanied by vomiting and diarrhea

Kidney damage can lead to proteinuria

Brain damage can cause cognitive deficits, seizures, or abnormal behaviors

 

Advantages Of Stem Cell Treatment For Autoimmune Diseases

 

At present, the clinical treatment of autoimmune disease is mainly with drug therapy, including glucocorticoids and various immunosuppressive agents. Drug therapy can only control the progression of the disease to a certain extent but cannot completely cure the disease. The immunosuppressive agents inhibit all the immune functions of the side effects and toxicity is relatively intensive.

 

Compared with conventional therapy, stem cell therapy has unique advantages:

  

Stem cell therapy

Conventional treatment

Curative Treatment or diseases management

Stem cell therapy is a new treatment for autoimmune diseases that aims to help restore normal function of the immune system by modulating immune system response and repairing/regenerating damaged cells and tissues in the body.

 

If you receive stem cell therapy at an early stage, it can reverse body damage caused by the immune response, thus reducing recurrence rates, freeing you from drug dependence, and even avoiding surgery.

The primary choice for autoimmune diseases is drug therapy. The main purpose of treatment is to inhibit the immune response and suppress inflammation in the body. Autoimmune diseases cannot be completely cured, and the recurrence rate is high.

Dosage

When stem cells are infused back into the body, they can regulate the immune system back to normal functionality, significantly reduce the recurrence rate, and decrease the drug dosage needed. If the therapy is conducted at an early stage of the disease, it can completely reverse the drug dependence.

 

Stem cell experts based on your current level of disease and other comorbidities will design a customized protocol and decide, the number of stem cells, source of stem cells, and cycles of stem cell therapy.

If you choose drug therapy, you will find the dose of the drug increase slowly and gradually, and you will gradually develop resistance and require larger dosages or more powerful drugs.

Side-effects

No Side-effects as stem cells are our cells that are used to treat the disease and regenerate lung tissue to regain proper functioning.

Drugs may have side effects on the body, such as chest tightness, shortness of breath, difficulty breathing, adverse skin reactions, and rapid decline in immune function. The side effects are tremendous.

Convenience

Stem cell therapy is performed by stem cell specialists which requires a special laboratory to process the stem cells and the medical set-up to extract and inject the stem cell.

 

The therapy is going to be injection-based and needs to be performed in a hospital.

It’s relatively easy to take medications, but the patient needs to take them repeatedly every day, which is prone to the development of drug dependence.

Longevity

If treated in the early stage, in the long run, stem cell therapy can eliminate drug dependence, restore normal immune system functions, and return the patient to a healthy life. After the functional recovery of the immune system, the patients can eliminate the drug dependence and significantly reduce the recurrence rate. This is a long-term effect.

 

If conducted at a later stage, stem cell therapy can still reduce drug dosage, and in rare cases, you might need several treatment regimens.

The effect of drug therapy is short-term, and patients need to take medications daily, once stopped, the symptoms will resume or even worsen. You need to take medications for the whole lifetime.

End-stage

Stem cells are a fundamental part of our body, and the main function of stem cells is to regulate the immune system and repair/regenerate damaged cells and help you avoid surgery.

If your symptoms are severe, surgery may be necessary, but surgery only helps to remove necrotic tissue but help little to heal the disease, your disease condition remains and continue to damage your body.

 

How Can Stem Cell Therapy For Autoimmune Diseases Work

 

Immunomodulatory mechanisms: Stem cells suppress autoimmune responses and regulate immune balance by directly engaging immune cells and secreting a variety of immunoregulatory factors, therefore preventing the progression of autoimmune diseases.

 

Multidirectional differentiation potential: Stem cells can migrate directionally into damaged tissues and differentiate into functional cells of the corresponding tissue through the induction of tissue microenvironment, integrate with in situ cells of damaged tissues, and repair or rebuild the structure and function of damaged tissues.

 

Promote angiogenesis: After infusion of stem cells to the patients with damaged heart, liver, kidney, brain, and lung, capillary regeneration can be found by angiography, indicating that stem cells can promote the regeneration of blood vessels in damaged tissue and improve blood circulation.

 

Antioxidative stress: After the stem cells were infused into the body, the content of superoxide dismutase in the blood increased, and the apoptotic cells in the heart, liver, and kidney tissues decreased. This result confirmed that stem cells have anti-oxidative stress and anti-apoptotic effects.

 

SQ1 Stem Cell Services

During the whole treatment process, we’ll provide complete and first-class medical services to you. And to ensure your treatment effect, you can consult your doctor any time after the treatment.

www.sq1stemcell.com/stem-cell-transplant-for-autoimmune-d...

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

Kampung Belukar, Alor Setar, Kedah, Malaysia.

 

Cissus quadrangularis L. Vitaceae. CN: [Malay - Pokok patah tulang, Sipatah-patah, Pokok buasir], Winged treebine, Veldt grape, Devil's backbone. Used in traditional medicine for the treatment of pile and fractured bones. Compounds that act as receptor antagonists of glucocorticoids have reduced the healing time of broken bones 30 to 50 percent in clinical trials.

 

Synonym(s):

Cissus bifida Schumach. & Thonn.

Cissus quadrangula L.

Cissus quadrangula Salisb.

Cissus succulenta (Galpin) Burtt-Davy

Cissus tetragona Harv.

Cissus tetraptera Hook.f.

Cissus triandra Schumach. & Thonn.

Vitis quadrangularis (L.) Wall. ex Wight

Vitis quadrangularis (L.) Morales

Vitis quadrangularis (L.) Wall. ex Wight

Vitis succulenta Galpin

 

Ref and suggested reading:

www.theplantlist.org/tpl/record/kew-2722833

www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?10622

en.wikipedia.org/wiki/Cissus_quadrangularis

repository.ipb.ac.id/bitstream/handle/123456789/46733/201...

 

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

Kampung Belukar, Alor Setar, Kedah, Malaysia.

 

Cissus quadrangularis L. Vitaceae. CN: [Malay - Pokok patah tulang, Sipatah-patah, Pokok buasir], Winged treebine, Veldt grape, Devil's backbone. Used in traditional medicine for the treatment of pile and fractured bones. Compounds that act as receptor antagonists of glucocorticoids have reduced the healing time of broken bones 30 to 50 percent in clinical trials.

 

Synonym(s):

Cissus bifida Schumach. & Thonn.

Cissus quadrangula L.

Cissus quadrangula Salisb.

Cissus succulenta (Galpin) Burtt-Davy

Cissus tetragona Harv.

Cissus tetraptera Hook.f.

Cissus triandra Schumach. & Thonn.

Vitis quadrangularis (L.) Wall. ex Wight

Vitis quadrangularis (L.) Morales

Vitis quadrangularis (L.) Wall. ex Wight

Vitis succulenta Galpin

 

Ref and suggested reading:

www.theplantlist.org/tpl/record/kew-2722833

www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?10622

en.wikipedia.org/wiki/Cissus_quadrangularis

repository.ipb.ac.id/bitstream/handle/123456789/46733/201...

  

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

What is Rheumatoid arthritis:

 

Rheumatoid arthritis is the most common inflammatory disease of the joints. The onset is often sudden with pain in the little finger or toe joints. This disease can also harm other joints of our body like hands or knees or shoulder or foot. The preference carpal bones with carpophalangeal joints and proximal interphalangeal joints are mainly affected by it. The fingers are not affected. The affected joints become swollen and are over-heated. Redness of the affected joints is quite possible. A symmetrical (occurring on both sides) synovitis originating from distant joints is typical but not mandatory. Patients can experience Rheumatoid arthritis symptoms like morning stiffness. In the course of the disease more and more joints are affected. This disease comes to patients in batches and it can stay up to few weeks or months. Any improvement of health is not dependent on the Rheumatoid arthritis treatments.

 

Commonly found Rheumatoid arthritis symptoms:

 

The causes of the disease are still largely unknown. The cause of this disease is assumed to be autoimmune. Some bodily substances are attacked like the articular cartilage from cells of the immune system. Viruses and bacteria are triggered by this disease similar to the pathogenesis of rheumatic fever. Now researchers are doing researches on the relationship between periodontal diseases and the emergence of rheumatoid arthritis. The twin studies being influenced by genes has been demonstrated many times. Rheumatoid arthritis is coupled with a few MHC or HLA alleles. The most important Rheumatoid arthritis symptoms are pain in the joints; stiffness felt in the morning for quite a few hours; fatigue and tiredness or even fever. Patients also face reduction of appetite and rapid weight reduction.

 

Essential Rheumatoid arthritis treatments:

 

In drug based Rheumatoid arthritis treatments traditionally four main groups of medications are identified:

 

* Analgesics (painkillers)

* Non-steroidal anti-inflammatory drugs NSAID

* Glucocorticoids

* Antirheumatic drugs

 

The targets and effects of all kinds of drugs are not same. The prescription of DMARDs is included with cortisone or cortisone free anti inflammatory drugs. Modern concepts of treatment of rheumatism are characterized by the fact that different methods are combined. Compilation of therapies of various diseases and situations help to provide better treatment. Rheumatoid surgery is established as a branch of Orthopedics. This surgery is mainly done by the doctors who are specialized in heavy and severe joints changes for the rheumatic disease.The synovial membrane – the inner layer of the capsule – is the actual location of the disease. It can affect the entire course if you want to remove this with the help of surgeries. Depending on the anatomy of the affected joint significant reduction of the diseased tissue usually has a soothing effect. Rheumatoid arthritis symptoms should not be neglected. Rheumatoid arthritis must be treated in shorter period of time as it is very dangerous.

 

RIUM, WP Kuala Lumpur, Malaysia.

 

Cissus quadrangularis L. Vitaceae. CN: [Malay - Pokok patah tulang, Sipatah-patah, Pokok buasir], Tikel balung, Sugpon-sugpon, Winged treebine, Veldt grape, Devil's backbone. Used in traditional medicine for the treatment of pile and fractured bones. Compounds that act as receptor antagonists of glucocorticoids have reduced the healing time of broken bones 30 to 50 percent in clinical trials.

 

Synonym(s):

Cissus bifida Schumach. & Thonn.

Cissus quadrangula L.

Cissus quadrangula Salisb.

Cissus succulenta (Galpin) Burtt-Davy

Cissus tetragona Harv.

Cissus tetraptera Hook.f.

Cissus triandra Schumach. & Thonn.

Vitis quadrangularis (L.) Wall. ex Wight

Vitis quadrangularis (L.) Morales

Vitis quadrangularis (L.) Wall. ex Wight

Vitis succulenta Galpin

 

Ref and suggested reading:

www.theplantlist.org/tpl/record/kew-2722833

www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?10622

en.wikipedia.org/wiki/Cissus_quadrangularis

repository.ipb.ac.id/bitstream/handle/123456789/46733/201...

Both adrenal glands sit atop the kidneys and are composed of an outer cortex and an inner medulla, all surrounded by a connective tissue capsule. The cortex can be subdivided into additional zones listed from superficial to deep: the zona glomerulosa that releases mineralocorticoids such as aldosterone to regulate mineral balance, the zona fasciculata that releases glucocorticoids such as cortisol, corticosterone, and cortisone to regulate glucose metabolism, and the zona reticularis that releases androgens such as dehydroepiandrosterone that stimulate masculinization. The adrenal medulla releases stress hormones such as epinephrine and norepinephrine that stimulate the sympathetic autonomic nervous system (ANS). LM × 204. (Image credit: "The Adrenal Glands" by Julie Jenks is licensed under CC BY 4.0 / A derivative from the original work / Micrograph provided by the Regents of University of Michigan Medical School © 2012)

Alor Setar, Kedah, Malaysia.

 

Cissus quadrangularis L. Vitaceae. CN: [Malay - Pokok patah tulang, Sipatah-patah, Pokok buasir], Winged treebine, Veldt grape, Devil's backbone. Used in traditional medicine for the treatment of pile and fractured bones. Compounds that act as receptor antagonists of glucocorticoids have reduced the healing time of broken bones 30 to 50 percent in clinical trials.

 

Synonym(s):

Cissus bifida Schumach. & Thonn.

Cissus quadrangula L.

Cissus quadrangula Salisb.

Cissus succulenta (Galpin) Burtt-Davy

Cissus tetragona Harv.

Cissus tetraptera Hook.f.

Cissus triandra Schumach. & Thonn.

Vitis quadrangularis (L.) Wall. ex Wight

Vitis quadrangularis (L.) Morales

Vitis quadrangularis (L.) Wall. ex Wight

Vitis succulenta Galpin

 

Ref and suggested reading:

www.theplantlist.org/tpl/record/kew-2722833

www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?10622

en.wikipedia.org/wiki/Cissus_quadrangularis

repository.ipb.ac.id/bitstream/handle/123456789/46733/201...

 

Vitamina D

La Vitamina D, conosciuta anche come la vitamina del sole, può essere prodotta dal corpo con l'esposizione solare o assunta tramite cibi o integratori.

Un adeguato apporto di vitamina D è importante per la regolazione dell'assorbimento del calcio e del fosforo, per il mantenimento di ossa e denti normali, e si pensa che porti un effetto protettivo contro molte malattie come il cancro, il diabete di tipo 1 e la sclerosi multipla.

 

La Vitamina D ha molti ruoli nel corpo umano, tra cui:

   

Mantenere la salute di ossa e denti

Supportare la salute del sistema immunitario, del cervello e del sistema nervoso

Regolare i livelli di insulina e aiutare a controllare la glicemia

Supportare la funzionalità polmonare e la salute cardiovascolare.

   

Nonostante il suo nome, la vitamina D è considerata un pro-ormone e non una vitamina. Questo perchè il corpo è in grado di produrre la propria vitamina D attraverso l'azione dei raggi solari, mentre le vitamine e i nutrienti non possono essere sintetizzati dal corpo ma essere assunti tramite l'alimentazione o l'integrazione.

 

Si stima che l'esposizione al sole a pelle nuda (e senza protezione solare) per 5-10 minuti 2-3 volte a settimana consenta al corpo di produrre sufficiente vitamina D. Purtroppo questa ha un'emivita di circa 2 settimane, per cui i depositi di vitamina D possono essere carenti, soprattutto di inverno.

 

Studi recenti suggeriscono che più del 50% degli adulti e dei bambini hanno una deficienza di vitamina D: molti fattori possono contribuire a questa condizione, come spiegheremo più avanti in questo articolo.

 

La Vitamina D viene prodotta quando la luce solare converte il colesterolo contenuto nella pelle in vitamina D3. A questo punto attraverso vari passaggi sia nel fegato che nei reni, la vitamina D3 viene convertita nella sua forma attiva. Per questo ci possono essere dei farmaci o delle patologie che interferiscono con la sintesi della vitamina D. Ad esempio le statine o altri farmaci che inibiscono la sintesi del colesterolo possono interferire con la reazione portata a termine dalla luce solare, oppure ci possono essere problemi al fegato o ai reni che inibiscono la sintesi della vitamina D.

 

Ecco alcuni punti chiave:

 

Una persona con la pelle chiara che espone totalmente il corpo al sole può sintetizzare fino a 20,000 UI di vitamina D3 in 20 minuti.

La carenza di vitamina D è comune, soprattutto negli anziani, nei bambini, nelle persone con la pelle scura o che si espongono poco al sole e nelle persone che vivono a elevate latitudini.

La carenza di vitamina D è stata riscontrata nell'80% delle persone con frattura dell'anca.

800 UI di vitamina D al giorno riducono il rischio di frattura del 20% nell'anziano e diminuiscono inoltre la probabilità di cadere.

Il metabolismo della vitamina D può essere alterato da alcuni farmaci, inclusi i barbiturici, il fenobarbital e le statine.

 

Possibili effetti benefici sulla salute della vitamina D

Questa sezione prende in esame i potenziali benefici per la salute della vitamina D, dalla salute ossea alla possibile prevenzione del cancro.

1) Vitamina D per la salute delle ossa

La vitamina D gioca un ruolo fondamentale nella regolazione del calcio e nel mantenimento dei normali livelli di fosforo nel sangue, due fattori estremamente importanti per mantenere delle ossa sane. Abbiamo bisogno di vitamina D per assorbire il calcio nell'intestino e per trattenere quello che sarebbe escreto attraverso i reni.

 

La carenza di vitamina D nei bambini può causare rachitismo, una malattia caratterizzata dalle gambe arcuate a causa dell'anomala mineralizzazione e della scarsa durezza dell'osso.

 

Negli adulti, la carenza di vitamina D si manifesta come osteomalacia o osteoporosi. L'osteomalacia risulta in una scarsa densità ossea, debolezza muscolare e spesso causa piccole pseudo fratture della colonna vertebrale, del femore e dell'omero. L'osteoporosi è il disturbo più comune tra le donne in post-menopausa e tra gli uomini anziani.

2) Ridotto rischio di influenza

E' stato studiato che nei bambini a cui sono state somministrate 1200 UI di vitamina D per 4 mesi durante l'inverno il rischio di influenza è ridotto del 40%.

3) Ridotto rischio di diabete

Molti studi osservazionali hanno mostrato una relazione inversa tra le concentrazioni di Vitamina D nel sangue e il rischio di diabete di tipo 2. Nei diabetici di tipo 2 scarsi livelli di vitamina D possono avere effetti avversi sulla secrezione di insulina e sulla secrezione di glucosio.

4) Bambini

Bassi livelli di vitamina D sono stati associati anche ad un alto rischio di sviluppare asma, dermatiti atopiche ed eczemi.

 

La vitamina D può aumentare gli effetti anti-infiammatori dei glucocorticoidi, rendendola un'ottima terapia di supporto per chi soffre di asma resistente.

5) Gravidanza

Le donne incinta che hanno una carenza di vitamina D sembrano avere un maggior rischio di sviluppare preeclampsia e di partorire con cesareo. Uno scarso livello di vitamina D è associato anche con diabete gestazionale e con vaginosi batteriche durante la gravidanza. E' inoltre importante sottolineare che anche un eccesso di vitamina D durante la gravidanza è nocivo: sembra infatti che sia associato con un maggior rischio che il nascituro sviluppi allergie alimentari durante i primi due anni di vita.

6) Prevenzione del cancro

La vitamina D è estremamente importante per regolare la crescita cellulare e la comunicazione tra le cellule. Alcuni studi hanno suggerito che la forma attiva di vitamina D può ridurre la progressione del cancro rallentando la crescita e lo sviluppo di nuovi vasi sanguigni nei tessuti tumorali, aumentando quindi la morte delle cellule cancerose e riducendo la proliferazione cellulare e le metastasi. La vitamina D influenza l'espressione di più di 200 geni umani, che può essere alterata quando il livello di vitamina D è subottimale.

   

La carenza di vitamina D è stata anche associata con un aumentato rischio di malattie cardiovascolari, ipertensione, sclerosi multipla, autismo, Alzheimer, artrite reumatoide e asma, anche se saranno necessari ulteriori studi per dimostrare il suo ruolo.

Apporto raccomandato di vitamina D

L'apporto raccomandato di vitamina D può essere misurato in due modi: in microgrammi (mcg) e unità internazionali (UI). 1 mcg di vitamina D equivale a 40 UI.

 

L'apporto di vitamina D consigliato dal Ministero della salute può essere così suddiviso per le diverse età

 

Neonati 0-12 mesi - 400 UI (10 mcg)

Bambini 1-18 anni - 600 UI (15 mcg)

Adulti di 70 - 600 UI (15 mcg)

Adulti over 70 - 800 UI (20 mcg)

Donne incinta o che allattano - 600 UI (15 mcg).

 

Anche se il corpo ha la capacità di produrre vitamina D ci sono molte ragioni per cui può sopraggiungere la sua carenza. I pigmenti scuri della pelle e l'uso dei filtri solari possono significativamente diminuire la capacità del corpo di assorbire la radiazione ultravioletta UVB, richiesta per la produzione di vitamina D.

 

Una protezione solare con protezione 30 (SPF 30) può ridurre la capacità del corpo di sintetizzare la vitamina del 95%. La pelle inoltre deve essere direttamente esposta al sole, non coperta da vestiti. Anche l'angolo con cui il sole colpisce la terra può influenzare l'assorbimento.

 

Persone che vivono al Nord o in aree di grande inquinamento, o che lavorano di notte e si riposano di giorno dovrebbero consumare altre fonti di vitamina D quando possibile. Anche bambini che sono esclusivamente allattati al seno sono ad alto rischio di sviluppare una carenza di vitamina D, soprattutto se hanno la pelle scura o una minima esposizione solare.

 

Per assumere la vitamina D con l'alimentazione bisogna considerare che non è importante solo il contenuto in vitamina D del singolo alimento, ma è la sinergia di nutrienti che ne migliora l'assorbimento e rende un cibo una parte importante della nostra dieta. Per esempio la vitamina D è liposolubile, cioè per essere assorbita necessita di alimenti grassi. In aggiunta il magnesio è fondamentale per convertire la vitamina D nella sua forma attiva.

Fonti alimentari di vitamina D

La più ricca fonte di vitamina D è il pesce grasso, ecco qui una lista di cibi con buoni livelli di vitamina D:

 

Olio di fegato di merluzzo, 1 cucchiaio: 1360 UI

Arringhe, fresche, crude, 115 g: 1056 UI

Pesce spada, cotto, 115 g: 941 UI

Funghi maitake crudi, 1 tazza: 786 UI

Salmone, rosso, cotto, 115 g: 596 UI

Sardine, in scatola, 115 g: 336 UI

Latte scremato fortificato, 1 tazza: 120 UI

Tonno in scatola, al naturale, sgocciolato,: 68 UI

Uovo grande, di gallina, intero: 44 UI.

  

Vitamina D3 per vegani

Vitamina D assunta tramite integratori alimentari

Non sempre si riesce ad introdurre una sufficiente dose di vitamina D con l'alimentazione, per questo in molti casi è opportuno assumere un integratore naturale a base di vitamina D3, che è la forma più efficace. La maggior parte degli integratori in commercio vengono estratti da grassi animali e sono quindi inutilizzabili da tutte le persone che hanno deciso di escludere gli esseri animali dalla propria alimentazione, per questo esistono degli integratori naturali a base di vitamina D3 estratta dai Licheni, quindi completamente vegetali ed adatti quindi sia a vegetariani che a vegani. www.phitaly.com/it/vitamine/vitamina-d3/

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bengkuang.com/the-causes-and-treatments-of-psoriasis/

Wu Ruxin, born in 1957, was infected by SARS virus in April, 2003. Because of extensive use of glucocorticoids in emergency treatment of SARS she was diagnosed as Femoral head necrosis. She went to the swimming pool because swimming is the best exercise to prevent them from muscular dystrophy and without a heavy load on their bones.

吴如欣，1957年生人，SARS期间她到医院看病过程中被意外感染。因在治疗过程中使用了大量激素，导致股骨坏死，一度瘫痪在床。经五年多的康复治疗，她的生活正在慢慢恢复正常，但提前退休的她每天下午都要去附近的游泳馆，游泳对后遗症患者来说是最好的运动，因为它不用负重又能防止肌肉萎缩。

Kampung Belukar, Alor Setar, Kedah, Malaysia.

 

Cissus quadrangularis L. Vitaceae. CN: [Malay - Pokok patah tulang, Sipatah-patah, Pokok buasir], Winged treebine, Veldt grape, Devil's backbone. Used in traditional medicine for the treatment of pile and fractured bones.Compounds that act as receptor antagonists of glucocorticoids have reduced the healing time of broken bones 30 to 50 percent in clinical trials.

 

Synonym(s):

Cissus bifida Schumach. & Thonn.

Cissus quadrangula L.

Cissus quadrangula Salisb.

Cissus succulenta (Galpin) Burtt-Davy

Cissus tetragona Harv.

Cissus tetraptera Hook.f.

Cissus triandra Schumach. & Thonn.

Vitis quadrangularis (L.) Wall. ex Wight

Vitis quadrangularis (L.) Morales

Vitis quadrangularis (L.) Wall. ex Wight

Vitis succulenta Galpin

 

Ref and suggested reading:

www.theplantlist.org/tpl/record/kew-2722833

www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?10622

en.wikipedia.org/wiki/Cissus_quadrangularis

repository.ipb.ac.id/bitstream/handle/123456789/46733/201...

  

Kampung Belukar, Alor Setar, Kedah, Malaysia.

 

Cissus quadrangularis L. Vitaceae. CN: [Malay - Pokok patah tulang, Sipatah-patah, Pokok buasir], Winged treebine, Veldt grape, Devil's backbone. Used in traditional medicine for the treatment of pile and fractured bones. Compounds that act as receptor antagonists of glucocorticoids have reduced the healing time of broken bones 30 to 50 percent in clinical trials.

 

Synonym(s):

Cissus bifida Schumach. & Thonn.

Cissus quadrangula L.

Cissus quadrangula Salisb.

Cissus succulenta (Galpin) Burtt-Davy

Cissus tetragona Harv.

Cissus tetraptera Hook.f.

Cissus triandra Schumach. & Thonn.

Vitis quadrangularis (L.) Wall. ex Wight

Vitis quadrangularis (L.) Morales

Vitis quadrangularis (L.) Wall. ex Wight

Vitis succulenta Galpin

 

Ref and suggested reading:

www.theplantlist.org/tpl/record/kew-2722833

www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?10622

en.wikipedia.org/wiki/Cissus_quadrangularis

repository.ipb.ac.id/bitstream/handle/123456789/46733/201...

 

Kampung Belukar, Alor Setar, Kedah, Malaysia.

 

Cissus quadrangularis L. Vitaceae. CN: [Malay - Pokok patah tulang, Sipatah-patah, Pokok buasir], Tikel balung, Sugpon-sugpon, Winged treebine, Veldt grape, Devil's backbone. Used in traditional medicine for the treatment of pile and fractured bones. Compounds that act as receptor antagonists of glucocorticoids have reduced the healing time of broken bones 30 to 50 percent in clinical trials.

 

Synonym(s):

Cissus bifida Schumach. & Thonn.

Cissus quadrangula L.

Cissus quadrangula Salisb.

Cissus succulenta (Galpin) Burtt-Davy

Cissus tetragona Harv.

Cissus tetraptera Hook.f.

Cissus triandra Schumach. & Thonn.

Vitis quadrangularis (L.) Wall. ex Wight

Vitis quadrangularis (L.) Morales

Vitis quadrangularis (L.) Wall. ex Wight

Vitis succulenta Galpin

 

Ref and suggested reading:

www.theplantlist.org/tpl/record/kew-2722833

www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?10622

en.wikipedia.org/wiki/Cissus_quadrangularis

repository.ipb.ac.id/bitstream/handle/123456789/46733/201...

  

Vue sur les zones glomérulée et fasciculée de la corticosurrénale. Les cellules de la zone glomérulée (tiers de l'image, en haut, en mauve foncé) sécrète des hormones (minéralocorticoïdes), comme l'aldostérone qui régule les taux de sodium et de potassium et augmente la tension artérielle. Celles de la zone fasciculée (reste de l'image, en mauve clair) synthétisent des glucocorticoïdes comme le cortisol qui augmente la glycémie et permet au corps de s'adapter à une augmentation d'activité !

 

En médecine, on prescrit des doses bien supérieures aux normes physiologiques pour diminuer l'inflammation et/ou les défenses immunitaires, avec de nombreux effets secondaires en cas d'administration prolongée !

 

- Afin de ne pas surcharger les images, celles-ci ne comportent qu'un minimum d'annotations, voire aucune. Pour plus de détails ou précisions, contacter Franck Genten : fgenten@gmail.com

- Site internet : histologie-histology.be

- Toutes les images originales HR sont disponibles sans annotations

-------------------------------------------------------------------------------------

View on the zona glomerulosa (top third of the picture, in dark pink) and the zona fasciculata (rest of the picture, in light pink).

The cells of the zona glomerulosa secrete hormones (mineralocorticoids), principally aldosterone which regulates the body sodium and potassium levels, and participates in blood pressure regulation. The cells of the zona fasciculata secretes glucocorticoid hormones, mainly cortisol which has numerous metabolic effects (raising blood glucose level and synthesis of glycogen).

 

Corticoids remain at the forefront of anti-inflammatory and immunosuppressive therapies, but, when chronically elevated (therapeutic doses), cortisol can have deleterious effects on weight, immune function, and chronic disease risk.

 

- In order not to overload the images, the latter do not contain any annotations, or the bare minimum. For more information or details, contact Franck Genten : fgenten@gmail.com

- Website : histologie-histology.be

- All the original pictures HR are available without annotations

- If you notice any mistake in the English text, please let me know. Thank you.

 

RIUM, WP Kuala Lumpur, Malaysia.

 

Cissus quadrangularis L. Vitaceae. CN: [Malay - Pokok patah tulang, Sipatah-patah, Pokok buasir], Tikel balung, Sugpon-sugpon, Winged treebine, Veldt grape, Devil's backbone. Used in traditional medicine for the treatment of pile and fractured bones. Compounds that act as receptor antagonists of glucocorticoids have reduced the healing time of broken bones 30 to 50 percent in clinical trials.

 

Synonym(s):

Cissus bifida Schumach. & Thonn.

Cissus quadrangula L.

Cissus quadrangula Salisb.

Cissus succulenta (Galpin) Burtt-Davy

Cissus tetragona Harv.

Cissus tetraptera Hook.f.

Cissus triandra Schumach. & Thonn.

Vitis quadrangularis (L.) Wall. ex Wight

Vitis quadrangularis (L.) Morales

Vitis quadrangularis (L.) Wall. ex Wight

Vitis succulenta Galpin

 

Ref and suggested reading:

www.theplantlist.org/tpl/record/kew-2722833

www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?10622

en.wikipedia.org/wiki/Cissus_quadrangularis

repository.ipb.ac.id/bitstream/handle/123456789/46733/201...