Kurzgesagt – In a Nutshell
Kurzgesagt – In a Nutshell
Embedded Files
Sources – Tuberculosis
Sources – Tuberculosis
We thank following expert for his feedback:
John Green
If you want to learn more about tuberculosis, check out his Crash Course episode: https://www.youtube.com/watch?v=7D-gxaie6UI and the organization Partners In Health: https://www.pih.org/programs/tuberculosis
– The white death has haunted humanity like no other disease following us for thousands, maybe millions of years. It was there when we tamed fire, invented culture, and ventured out of Africa to conquer the world
#Barberis, I. et al. The History of Tuberculosis: From the First Historical Records to the Isolation of Koch's Bacillus. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432783/
Quote: “It has been hypothesized that the genus Mycobacterium originated more than 150 million years ago.”
“Three million years ago, an early progenitor of Mycobacterium tuberculosis might have infected early hominids in East Africa and 20.000-15.000 years ago, for the first time, the common ancestor of modern strains of MT might have appeared”.
– In 1815 it caused one in four deaths in Britain.
Tuberculosis was commonly called “consumption” before 1900 because patients lost weight and seemed to be “consumed” by the disease.
#Daskalopoulos M, et al. Tuberculosis - General Facts - Historical Background. 2024
https://ijssrr.com/journal/article/view/1382/1199
Quote: “In 1815, one in four deaths in England was due to "consumption".
#John F. Murray. A Century of Tuberculosis. 2004
https://www.atsjournals.org/doi/full/10.1164/rccm.200402-140o
Quote: “Mortality from tuberculosis was colossal: one of every four deaths recorded in parish registries from England at the end of the eighteenth century was attributed to the disease.”
– In the last 200 years it killed a billion people, way more than all wars and natural disasters combined.
#Paulson, Tom. Epidemiology: A Mortal Foe. 2013
https://www.nature.com/articles/502S2a#:~:text=Tuberculosis%20has%20killed%20more%20than,2
Quote: “Tuberculosis has killed more than any other infectious disease in history. Over a billion lives in the past two hundred years.”
#Bastian Herre, et al. War and Peace. 2023
https://ourworldindata.org/war-and-peace
Quote: “Since 1800, more than 37 million people worldwide have died while actively fighting in wars.”
The number of deaths from natural disasters since 1900 are around 10,58 millions in total. There is no data for the years prior to 1900, although it should be similar to the numbers around the beginning of the 20th century.
Even if we take the higher value of half a million per year, we still have 100 million deaths for the last two centuries. It is still well below the number of deaths from TB.
#Hannah Ritchie and Pablo Rosado. Natural disasters. 2022, revised 2024.
https://ourworldindata.org/natural-disasters#number-of-deaths-from-natural-disasters
Quote: “In the early 1900s, the annual average was often in the range of 400,000 to 500,000 deaths. In the second half of the century and into the early 2000s, we have seen a significant decline to less than 100,000 – at least five times lower than these peaks.”
– Even today it’s the infectious disease with the highest kill count.
Up until Covid-19, TB has been the leading cause of death within infectious diseases. We don’t yet have the mortality numbers for 2023 for both diseases and it is still debated whether Covid-19 or TB was the top killer. However, TB is the second cause of death by infectious disease after COVID in 2022. But because of the historic lead of TB, we took it as the top killer.
#WHO. Global tuberculosis report 2023. 2023
Quote: “The latest year for which WHO has published estimates of global deaths by cause remains 2019, when TB was the top cause of death from a single infectious agent and the 13th leading cause of death worldwide (Fig. 1.2.4). In 2022, it is anticipated that TB will rank second as a cause of death from a single infectious agent, after COVID-19 (3).”
#WHO. Global tuberculosis report 2023. 2023
Quote: “Globally, the annual number of deaths caused by TB fell between 2010 and 2019, but this trend was reversed in 2020 and 2021 (Fig. 1.2.1). The estimated increase in the number of deaths caused by TB in these two years was the consequence of disruptions to TB diagnosis and treatment during the COVID-19 pandemic, when the reported number of people newly diagnosed with TB fell from 7.1 million in 2019 to 5.8 million in 2020 and 6.4 million in 2021 (Section 2.1), suggesting a large increase in the number of people with undiagnosed and untreated TB. The estimated decrease in the number of deaths caused by TB in 2022 (a 6.4% reduction compared with 2021) reflects the big global recovery in the number of people newly diagnosed with TB in 2022 (Section 2.1).”
The following chart shows a cumulative sum of the number of deaths in 2022, as 6.73 million - 5.45 million = 1.28 million.
#OWID. Coronavirus (COVID-19) Deaths. Retrieved March 2024.
– But… Do you even know what we are talking about? We’re talking about Mycobacterium tuberculosis which causes tuberculosis or TB – our original arch enemy.
Mycobacteria are a type of bacteria. They are different though since they have an outer membrane, they do not have capsules, most do not form endospores and have a cell wall that is thicker than in many other bacteria, which is composed of peptidoglycan and lipids.
Ziehl-Neelsen staining of Mycobacterium tuberculosis, as seen through a microscope.
https://www.osmosis.org/learn/Mycobacterium_tuberculosis_(Tuberculosis)
– Right now one in four humans alive are infected with the bacterium
#WHO. 10 facts on tuberculosis. 2023
https://www.who.int/news-room/facts-in-pictures/detail/tuberculosis
Quote: “About one quarter of the world’s population is infected with tuberculosis (TB) bacteria. Only a small proportion of those infected will become sick with TB.”
The Perfect Human Predator
– Usually the bacterium enters your body through the airways and sets up home in the lungs, a giant living cave system, defended by billions of macrophages, powerful guard cells that hunt and kill intruders
#Rishi Desai, et al. Mycobacterium tuberculosis (Tuberculosis). 2023
https://www.osmosis.org/learn/Mycobacterium_tuberculosis_(Tuberculosis)
#R. Alsayed, Shahinda S., and Hendra Gunosewoyo. Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10049048/
Quote: “Following the M. tb transmission to the new host, the bacilli enter the lung and get ingested by macrophages.”
– The TB bug is quickly attacked and devoured alive. Unfortunately this is its plan. The white death is the worst kind of parasite – an immune system parasite.
– The TB bug is quickly attacked and devoured alive. Unfortunately this is its plan. The white death is the worst kind of parasite – an immune system parasite.
#Rishi Desai, et al. Mycobacterium tuberculosis (Tuberculosis). 2023
https://www.osmosis.org/learn/Mycobacterium_tuberculosis_(Tuberculosis)
Zhai W, et al. The Immune Escape Mechanisms of Mycobacterium Tuberculosis. 2019 https://pubmed.ncbi.nlm.nih.gov/30650615
Quote: “Epidemiological data from the Center of Disease Control (CDC) and the World Health Organization (WHO) statistics in 2017 show that 10.0 million people around the world became sick with tuberculosis. Mycobacterium tuberculosis (MTB) is an intracellular parasite that mainly attacks macrophages and inhibits their apoptosis. It can become a long-term infection in humans, causing a series of pathological changes and clinical manifestations.”
– But TB evolved a thick, waxy coat that makes it completely immune to those acids. Worse, it captures and modifies the Macrophage to be a perfect host. Like a tiny vampire, the parasite slowly consumes the cell.
– But TB evolved a thick, waxy coat that makes it completely immune to those acids. Worse, it captures and modifies the Macrophage to be a perfect host. Like a tiny vampire, the parasite slowly consumes the cell.
Macrophages phagocite Mycobacterium tuberculosis (mTB), but once mTB is inside the macrophage, it produces a protein that inhibits the fusion with the lysosome, hindering its demise. mTB not only survives, but also starts proliferating inside the macrophage. Also the composition of the cell wall of TB helps the mycobacterium resist the attack of the immune system.
#Ghazaei, Ciamak. Mycobacterium Tuberculosis and Lipids: Insights into Molecular Mechanisms from Persistence to Virulence. 2018 https://doi.org/10.4103/jrms.JRMS_904_17.
Quote: “The unique composition of the cell wall composed of mycolic acid, glycolipids such as diacyltrehaloses, polyacyltrehalose, lipomannan, lipoarabinomannan (LAM), mannose-capped-LAM, sulfolipids, and trehalose-6,6’-dimycolate, all have been implicated in providing the pathogen an advantage in the host.”
#Yuefeng Ji, et al. Recent Progress in Identifying Bacteria with Fluorescent Probes. 2022
#Kenneth Murphy, Casey Weaver. Janeway's immunobiology 9th Edition. 2017
https://inmunologos.files.wordpress.com/2020/08/janeways-immunobiology-9th-ed_booksmedicos.org_.pdf
Quote: “Mycobacteria are engulfed by macrophages but resist being destroyed by preventing the intracellular vesicles in which they reside from fusing with lysosomes containing bactericidal agents. Thus the bacteria are protected from being killed. In resting macrophages, mycobacteria persist and replicate in these vesicles.”
– TB then replicates extremely slowly. Other microbes that make you sick multiply up to 60 times faster, exploding their numbers before the immune system can eradicate them. But the white death is so well adapted to you, it has already won by being here. No need to rush things.
E. coli has a doubling time of around 20 min in the lab. It is one of the fastest, whereas M. tuberculosis does so in about a day.
#Manlu Zhu & Xiongfeng Dai. On the intrinsic constraint of bacterial growth rate: M. tuberculosis’s view of the protein translation capacity. 2018
https://www.tandfonline.com/doi/full/10.1080/1040841X.2018.1425672
Quote: “Fast-growing bacteria species such as Escherichia coli can have a shortest generation time of 20 min. Slow-growing bacteria species are perhaps best known for Mycobacterium tuberculosis, a human pathogen with a generation time being no less than 16 h.”
#Ditse Z, Lamers MH, Warner DF. DNA Replication in Mycobacterium tuberculosis. 2017
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507077/
Quote: “M. tuberculosis divides every ∼18 to 24 hours during optimal growth in vitro, a period in which the bacillus undergoes a single round of chromosomal replication (29) with an accompanying mutation rate of ∼10^−10 errors per base pair per round of replication (70).“
#Gibson, Beth, et al. The Distribution of Bacterial Doubling Times in the Wild. 2018
– When its host cell is sucked dry and dies, the bacteria infect new Macrophages. Although these bacteria are stealthy, the decaying corpses they leave behind do activate a proper immune response – your body knows something is up and mobilizes its forces. But once again, this is part of the plan.
Macrophages and many other immune cells try to kill the bacteria, but that thick cell wall makes them a formidable fortress and resistant to many attacks. And it infects its attackers in the process. So when your cells can’t kill them they do the next best thing: keep the parasites from escaping.
#R. Alsayed, Shahinda S., and Hendra Gunosewoyo. Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets. 2024.
Quote: (Figure caption) “Pathophysiology of pulmonary TB. Following the M. tb transmission to the new host, the bacilli enter the lung and get ingested by macrophages. Further immune cells are recruited to wall off the infected macrophages, leading to the formation of the granuloma, the hallmark of TB. Healthy individuals remain latently infected, and the infection is kept at bay at this stage, but it is prone to the risk of reactivation. Foamy macrophages release their lipid content when they necrotise, leading to caseation (cheese-like structure). Caseum is a decay manifested at the core of the granuloma that compromise its rigid integrity. As the granuloma develops, the bacilli commence to seep out of the macrophages into the caseum layer. When the reactivation occurs, M. tb proliferates and the bacterial load becomes overwhelmingly high, whereupon the granuloma rupture, disseminating the bacteria to the airways. The bacilli are then expectorated as contagious aerosol droplets, restarting the cycle, infecting other individuals.”
– A granuloma is formed, a sort of white blob. In the center is a core of infected and dead Macrophages – a pleasant home and food for the bacterium. Other immune cells surround this sphere of death to contain it – creating a safespace where TB can sit for years.
#Stewart, Graham R., et al. Tuberculosis: A Problem with Persistence. 2003
#R. Alsayed, et al. Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10049048/
Quote: “Further immune cells are recruited to wall off the infected macrophages, leading to the formation of the granuloma, the hallmark of TB. Healthy individuals remain latently infected, and the infection is kept at bay at this stage, but it is prone to the risk of reactivation.”
[...]
“However, the bacteria still survive, avoiding death by blocking the phagolysosome fusion and subverting the host’s immune response.”
# Kenneth Murphy, et al. Janeway's immunobiology 9th Edition. 2017
https://inmunologos.files.wordpress.com/2020/08/janeways-immunobiology-9th-ed_booksmedicos.org_.pdf
Quote: “Granulomas form when an intracellular pathogen or its constituents cannot be completely eliminated. When mycobacteria (red) resist the effects of macrophage activation, a characteristic localized inflammatory response called a granuloma develops. This consists of a central core of infected macrophages. The core may include multinucleate giant cells, which are fused macrophages, surrounded by large macrophages often called epithelioid cells, but in granulomas caused by mycobacteria the core usually becomes necrotic. Mycobacteria can persist in the cells of the granuloma. The central core is surrounded by T cells, many of which are CD4-positive.”
– Worse, it is perfectly protected from medication and releases chemicals that make it hard for your heavy immune weapons to be activated. This is the stalemate version of Tuberculosis. The infection is sleeping and the bacteria is doing its thing.
#Pai, Madhukar, et al. Tuberculosis. 2016
https://doi.org/10.1038/nrdp.2016.76
Quote: “The granuloma illustrates the duality of M. tuberculosis infection: from the host's perspective, the granuloma is a bacterial ‘prison’ with the potential to ‘wall off’ infection from the rest of the body; however, from the bacterial perspective, it is a growing collection of phagocytic cells to infect and replicate within.”
#MSD Manual's Editorial Staff. Tuberculosis. 2022
https://www.msdmanuals.com/home/quick-facts-infections/tuberculosis-and-leprosy/tuberculosis-tb
Quote: “Your body may eventually kill the bacteria, but the bacteria often stay alive and inactive for many years.”
#David P. Maison. Tuberculosis pathophysiology and anti-VEGF intervention. 2022.
https://www.sciencedirect.com/science/article/pii/S2405579422000055#s0010
Quote: “A granuloma, as an analogy, is a bacterial jail that intends to imprison a bacteria inside a wall of immune cells. [2] The IFNɣ from the TH1 response will allow the maturation of the phagolysosome in the macrophages, cause the macrophage to produce nitric oxide via nitric oxide synthase, and induce autophagy. [15] The activated macrophages, now being unable to eliminate the pathogen, will release TNF alpha (TNFα). TNFα induces differentiation of monocytes into epithelioid histiocyte cells that form caseating granulomas to contain M. tuberculosis. [9], [15] Some of these epithelioid histiocyte cells fuse to form giant cells. [15] The TNFα continues a feedback chain by recruiting more monocytes to replace the newly differentiated monocytes. [15] The granuloma itself is formed from both macrophages and lymphocytes surrounding and containing M. tuberculosis. Cells involved in the granuloma include TH1, regulatory T cells (Treg), natural killer (NK) cells, B cells, Giant cells, dendritic cells, neutrophils, macrophage, foam cells, and epithelioid macrophage (Fig. 1E). The hypoxic environment within the granuloma temporarily restricts the growth of M. tuberculosis [4], but may also further promote angiogenesis into the tuberculoma. Unfortunately, within the granuloma, the necrotic pool serves as a nutrient source and protective barrier for this pathogen. Additionally, the eventual vasculature amplifies the nutrient supply to the bacteria.”
– This is going on right now in up to two billion people! But in one in ten of them, the disease will become active.
#TB Alliance. TB is a Pandemic. 2024
Quote: “The World Health Organization estimates that 1.8 billion people—close to one quarter of the world's population—are infected with Mycobacterium tuberculosis.”
#WHO. Tuberculosis. 2023
https://www.who.int/news-room/fact-sheets/detail/tuberculosis
Quote: “About 5–10% of people infected with TB will eventually get symptoms and develop TB disease.”
– Active Tuberculosis is an emergency. But again, a slow one. If your immune system can’t contain the infection anymore, granulomas burst. Suddenly your lungs are filled with Macrophage corpses and fresh bacteria. Your immune system panics and overreacts. Hordes of soldiers leave your blood and rush to the infected areas. They order inflammation and fluids flood into your lungs. But unfortunately, your lungs are not made to be a battlefield. In their panic, your immune cells don’t care – they’re running around with flamethrowers, trying to purge the infection but causing terrible damage.
#Pai, Madhukar, et al. Tuberculosis. 2016
Quote: “b | The bacteria replicate within the growing granuloma. If the bacterial load becomes too great, the granuloma will fail to contain the infection and bacteria will disseminate eventually to other organs, including the brain. At this phase, the bacteria can enter the bloodstream or re-enter the respiratory tract to be released — the infected host is now infectious, symptomatic and is said to have active TB disease.”
#R. Alsayed, et al. Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10049048/
Quote: “Foamy macrophages release their lipid content when they necrotise, leading to caseation (cheese-like structure). Caseum is a decay manifested at the core of the granuloma that compromise its rigid integrity. As the granuloma develops, the bacilli commence to seep out of the macrophages into the caseum layer. When the reactivation occurs, M. tb proliferates and the bacterial load becomes overwhelmingly high, whereupon the granuloma rupture, disseminating the bacteria to the airways. The bacilli are then expectorated as contagious aerosol droplets, restarting the cycle, infecting other individuals.”
#Chandra, Pallavi, et al. Immune Evasion and Provocation by Mycobacterium Tuberculosis. 2022
https://doi.org/10.1038/s41579-022-00763-4
Quote: “When growing extracellularly in cavities, M. tuberculosis reaches burdens of 107–109 bacilli. The development of cavities requires a tissue-damaging immune response directed against viable M. tuberculosis or M. tuberculosis antigen.”
“In addition, high levels of IL-1β and TNF, which are usually considered host protective, are associated with cavitary disease. TNF can drive necrotic cell death and expression of matrix metalloproteinases to promote tissue destruction.”
– As fluids and dead tissue amass, it becomes difficult to breathe and you begin coughing hard, sometimes even coughing up blood. And again this is part of the plan because now you spread millions of bacteria catching rides in tiny droplets.
#Sakamoto, K. The Pathology of Mycobacterium Tuberculosis Infection. 2012.
https://doi.org/10.1177/0300985811429313.
Quote: “The most common form of secondary tuberculosis is usually limited to the lung, and lesions begin as an exudative bronchopneumonia and progress to classical caseous granuloma formation, followed by massive necrosis and cavity formation. Eventually, there is breakdown of the fibrous capsule and communication with airways. These events allow for rapid growth of extracellular bacilli and spread into airways, leading to transmission or intrapulmonary spread.”
“...secondary cases are characterized by localized symptoms, such as coughing, hemoptysis, and pleuritic pain, as well as the generalized symptoms of fever, anorexia, night sweats, and cachexia. This propensity of TB to cause wasting away of patients garnered it the name consumption. In immunocompetent individuals, secondary TB can result in dissemination and death in 50% of cases and chronicity in 25% to 30% of cases. If the host is able to reestablish immune control over the disease, recovery is also possible, as is seen in 20% to 25% of cases.”
#Maria Villarreal. Bronchopneumonia: What Is It, Contagiousness, Diagnosis, Treatment, and More. ND
#Pagán, Antonio J., and Lalita Ramakrishnan. Immunity and Immunopathology in the Tuberculous Granuloma. 2015.
https://doi.org/10.1101/cshperspect.a018499
Quote: “TNF excess and strong T-cell immunity can lead to macrophage necrosis and release of mycobacteria into the extracellular space, where they can grow relatively unchecked. Subsequent induction of MMP1 causes granuloma cavitation and release of mycobacteria into the airways.”
#Miranda, Mayra S., et al. The Tuberculous Granuloma: An Unsuccessful Host Defence Mechanism Providing a Safety Shelter for the Bacteria?. 2012 https://doi.org/10.1155/2012/139127
Quote: “The bacteria can survive for decades inside the granuloma in a latent state. Due to some environmental (e.g., HIV infection, malnutrition etc.) or genetic factors, the bacteria will reactivate and provoke the death of the infected macrophages. A necrotic zone (called caseum due to its milky appearance) will develop in the centre of the granuloma (d). Ultimately the structure will disintegrate allowing exit of the bacteria, which will spread in other parts of the lungs and more lesions will be formed. Infection will also be transmitted to other individuals due to release of the infected droplets by coughing (e).”
#Urbanowski, Michael E., et al. Cavitary Tuberculosis: The Gateway of Disease Transmission. 2020
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30148-1/abstract
Quote: “A tuberculosis cavity is a pathological, gas-filled space in the lung parenchyma with a border resulting from M tuberculosis infection.”
“Apart from providing a growth niche, the cavity airspace is not useful for respiration. During cavity formation, both the basement membrane and alveolar architecture are permanently destroyed. Even after successful tuberculosis treatment, tuberculosis cavities can persist, leading to lifelong pulmonary deficits and recurrent opportunistic infections.”
– You burn a high fever and lose weight as your body is severely stressed. You turn into a ghost version of yourself. Even if you are treated, this phase can last weeks to months and is very serious. Insufficiently treated, TB will over months, years, or even decades slowly overtake your body.
#Edward A. Nardell. Tuberculosis. 2022
https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb
Quote: “In active pulmonary tuberculosis, even moderate or severe disease, patients may have no symptoms, except “not feeling well,” along with anorexia, fatigue, and weight loss, which develop gradually over several weeks, or they may have more specific symptoms. Cough is most common. At first, it may be minimally productive of yellow or green sputum, usually when awakening in the morning, but cough may become more productive as the disease progresses. Hemoptysis occurs only with cavitary TB (due to granulomatous damage to vessels but sometimes due to fungal growth in a cavity).”
“Low-grade fever is common but not invariable. Drenching night sweats are a classic symptom but are neither common in nor specific for TB. Dyspnea may result from lung parenchymal damage, spontaneous pneumothorax, or pleural TB with effusion.”
#CDC. Tuberculosis. 2017
https://www.cdc.gov/tb/topic/basics/exposed.htm
Quote: “Some people develop TB disease soon (within weeks) after becoming infected, before their immune system can fight the TB bacteria. Other people may get sick years later, when their immune system becomes weak for another reason.”
“Overall, without treatment, about 5 to 10% of infected persons will develop TB disease at some time in their lives. About half of those people who develop TB will do so within the first two years of infection.”
#Rodriguez, C. A., et al. Survival of People with Untreated TB: Effects of Time, Geography and Setting. 2023
https://doi.org/10.5588/ijtld.22.0668.
Quote: “Ten-year survival was 69% in North America (95% CI 54–81) and 36% in Europe (95% CI 10–71). Only 38% (95% CI 18–63) of non-sanitorium individuals survived to 10 years compared to 69% (95% CI 41–87) of sanitoria/hospitalized patients.”
#Moosazadeh, Mahmood, et al. Survival and Predictors of Death after Successful Treatment among Smear Positive Tuberculosis: A Cohort Study. 2014
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258661/
Quote: “...the survival rate in 11 years after successful treatment was 70%.”
– Especially for children or those already weakened, this can be too much and the disease wins the war. The bacterium spreads to other organs, lung function breaks down and the patient dies. 1.3 million people died this way in 2023 alone.
The WHO released the 2023 report in November 2023, with data of 2022, which is 1.3 million people. The estimated annual death rate of TB is about 1.5 million people.
#WHO. Tuberculosis. Retrieved March 2024.
https://www.who.int/health-topics/tuberculosis#tab=tab_1
Quote: “Every year, 10 million people fall ill with tuberculosis (TB). Despite being a preventable and curable disease, 1.5 million people die from TB each year – making it the world’s top infectious killer.”
#WHO. Tuberculosis. 2023
https://www.who.int/news-room/fact-sheets/detail/tuberculosis
Quote: “A total of 1.3 million people died from TB in 2022 .”
#WHO. Global Tuberculosis Report 2023. 2023
https://iris.who.int/bitstream/handle/10665/373828/9789240083851-eng.pdf?sequence=1
Quote: “The probability of developing TB disease is much higher among people living with HIV, and among people affected by risk factors such as undernutrition, diabetes, smoking and alcohol consumption.”
“Without treatment, the death rate from TB is high (about 50%) (7).”
#Barry Zingman, et al. Tuberculosis. Cedars Sinai. https://www.cedars-sinai.org/health-library/diseases-and-conditions/t/tuberculosis-tb.html
Quote: “The chance of developing active TB increases in babies and children and in older adults. It also increases in people with a weak immune system, especially those with HIV.”
“If TB of the lung is not treated early or if treatment isn’t followed, long-lasting (permanent) lung damage can result. TB can also cause infection of the bones, spine, brain and spinal cord, lymph glands, and other parts of the body. It can damage those areas and cause short-term (temporary) or permanent symptoms from the damage. Uncontrolled TB can lead to death.”
– The symptoms are often mild for many months, so you don’t feel in danger. Tuberculosis doesn’t want to kill you of course, it wants to stay alive and spread. And to do this, it exploits human behavior: The people you are most likely to infect are your family and friends, coworkers or neighbors, the people you spend a lot of time with. When Covid brought the world to a halt, the average patient infected 2-3 people. An active TB patient infects 5 -15 people in a year.
#WHO. Tuberculosis Q&A. 2018
https://www.who.int/news-room/questions-and-answers/item/tuberculosis
Quote: “When a person develops active TB (disease), the symptoms (cough, fever, night sweats, weight loss etc.) may be mild for many months.”
#Mayo Clinic. Tuberculosis. 2023
https://www.mayoclinic.org/diseases-conditions/tuberculosis/symptoms-causes/syc-20351250
Quote: “Tuberculosis can spread when a person with the illness coughs, sneezes or sings. This can put tiny droplets with the germs into the air. Another person can then breathe in the droplets, and the germs enter the lungs. Tuberculosis spreads easily where people gather in crowds or where people live in crowded conditions.”
“The disease is more likely to spread when people spend a lot of time together in an indoor space. So the disease spreads easily in places where people live or work together for long periods.”
The calculated reproductive number of coronavirus varies but the mean is calculated to be around 2,87, meaning each person can infect between 2 and 3 people. This number was higher during the high-phase of the pandemic.
#Billah, Md. A. et al. Reproductive Number of Coronavirus: A Systematic Review and Meta-analysis Based on Global Level Evidence. 2020. https://doi.org/10.1371/journal.pone.0242128
Quote: “The estimated summary reproductive number was 2.87.”
#WHO. Tuberculosis Q&A. 2018
https://www.who.int/news-room/questions-and-answers/item/tuberculosis
Quote: “People ill with TB can infect up to 10-15 other people through close contact over the course of a year.”
– Most people catch it via breathing tiny droplets from a cough or sneeze. This is especially common in crowded, poorly ventilated housing or workplaces. Which is why TB exploded during the Industrial Revolution. And indeed wherever we see new unplanned and overcrowded urbanization, from Lagos to St. Petersburg, we tend to see a rise of the White Death alongside it.
#Barberis, I., et al. The History of Tuberculosis: From the First Historical Records to the Isolation of Koch's Bacillus. 2017
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432783/
Quote: “During the industrial revolution, the diffusion of particularly problematic social conditions, such as extremely deprived work settings, poorly ventilated and overcrowded housing, primitive sanitation, malnutrition and other risk factors, were intimately associated with the disease.”
#Johan P. Mackenbach. Chapter 5 Health Problems of Industrializing Societies
In: A History of Population Health. 2020
https://brill.com/display/book/9789004429130/BP000007.xml
Quote: “However, as a result of industrialization and urbanization tuberculosis became much more prevalent, and much more important as a cause of death, in the 18th and 19th centuries. Overcrowded housing, exposure to dust in mining and other occupations, and a rise of excessive alcohol consumption – to name just a few side-effects of the Industrial Revolution – increased the likelihood of tuberculosis transmission as well as the likelihood of a fatal outcome of the disease. The resulting rise of mortality can clearly be seen in Swedish mortality data, which show an increase in mortality from respiratory tuberculosis between ca. 1750 and ca. 1850. In many other countries, this rise probably occurred before the start of national cause-of-death registration, but a rise can be witnessed in a few other European countries as well, such as Norway and Portugal where mortality rose until ca. 1900 and ca. 1930, respectively.”
But a study found that TB was already on the rise before the industrial revolution, at least in France.
#Dutour O, et al. Was the rise of TB contemporaneous with the industrial revolution? Epidemiological evolution of TB in France (17th-20th centuries) inferred from osteoarchaeological and historical archives. 2021
https://pubmed.ncbi.nlm.nih.gov/34243132/
Quote: “The epidemiological assertion that tuberculosis increased with the Industrial Revolution in cities must be reevaluated. In France, and perhaps in other cities, it was an endemic disease at least a century before, and associated with a higher mortality rate.”
#Aliyu, Alhaji A. Urbanization, Cities, and Health. The Challenges to Nigeria – A Review. 2017
Quote: “...the pace of urbanization is unprecedented with cities such as Lagos having annual urban growth rate of 5.8%.”
“This has created urban health crises of inadequate water safe supply, squalor and shanty settlements, sanitation, solid waste management, double burden of diseases and inefficient, congested, and risky transport system.”
#Sinkov, V., et al. New epidemic cluster of pre-extensively drug resistant isolates of Mycobacterium tuberculosis Ural family emerging in Eastern Europe. 2018. https://doi.org/10.1186/s12864-018-5162-3
Quote: “We hypothesize that both Clades A and B started their circulation within the same time period, likely at the end of the 19th – beginning of the twentieth century, coinciding with or fueled by accelerated industrialization in the Russian Empire.”
– Today most cases of active Tuberculosis – the version that spreads the disease further can be cured with a four-month regimen of four different antibiotics.
#Rishi Desai, et al. Mycobacterium tuberculosis (Tuberculosis). 2023
https://www.osmosis.org/learn/Mycobacterium_tuberculosis_(Tuberculosis)
Treatment of TB takes months. Depending on the severity of the case, the recommendation is at least 4 months.
#Mayo Clinic. Tuberculosis. 2023
https://www.mayoclinic.org/diseases-conditions/tuberculosis/diagnosis-treatment/drc-20351256
Quote: “Active TB disease may be treated for four, six or nine months.”
“Active TB disease requires taking several drugs.”
#WHO. Global Tuberculosis Report 2023. 2023
https://iris.who.int/bitstream/handle/10665/373828/9789240083851-eng.pdf?sequence=1
Quote: ”The latest WHO guidelines (5) include a strong recommendation for a 6-month regimen of isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) for people with drug-susceptible TB (both pulmonary and extrapulmonary): all four drugs for the first two months, followed by H and R for the remaining 4 months. They also include newer recommendations that people aged 12 years and older with drug-susceptible pulmonary TB may be treated with a 4-month regimen of rifapentine (P), H, Z and moxifloxacin (M), and that children and adolescents between 3 months and 16 years of age with non-severe TB (and without suspicion or evidence of resistance to R and H) may be treated with a 4-month regimen (2 months of H, R, Z and sometimes also E, followed by 2 months of H and R). Treatment success rates of at least 85% for people enrolled on the 6-month regimen are regularly reported to WHO by its 194 Member States.”
For patients with multidrug resistant TB or rifampicin resistant TB, a 6 month combination of bedaquiline, pretomanid, linezolid and moxifloxacin is recommended.
#WHO. Global Tuberculosis Report 2023. 2023
https://iris.who.int/bitstream/handle/10665/373828/9789240083851-eng.pdf?sequence=1
Quote: “Treatment for people diagnosed with R-resistant TB (RR-TB) and multidrug- resistant TB (MDR-TB, defined as resistance to H and R) requires other regimens.
The latest WHO guidelines (6) prioritize a new 6-month regimen consisting of bedaquiline (B), pretomanid (Pa),linezolid (L) and moxifloxacin (M), referred to as BPaLM; for people who have pre-extensively drug-resistant TB(pre-XDR-TB, defined as TB that is resistant to R and any fluoroquinolone), the regimen can be used without moxifloxacin (BPaL). Based on currently available safety data, this regimen is recommended only for people aged 14 years and above. For people not eligible for the 6-month regimen, other 9-month or longer regimens can be used (6). Nationally, treatment success rates for RR-TB reported to date have typically been in the range of 50–75%; the global average has been improving in recent years, reaching 63% in the most recent patient cohort for which data are available. This may further improve with expanded use of BPaLM, for which clinical trial data showed a treatment success rate of 89% (7). Treatment for XDR-TB (resistance to R, any fluoroquinolone and at least one of bedaquiline or linezolid) remains much more difficult and treatment success rates are typically low.”
[...]
Quote: “Drug-resistant TB continues to be a public health threat. Resistance to rifampicin – the most effective firstline drug – is of greatest concern. TB that is resistant to rifampicin and isoniazid is defined as multidrug-resistant TB (MDR-TB). Both MDR-TB and rifampicin-resistant TB (RR-TB) require treatment with second-line drugs. Globally, the estimated annual number of people who developed MDR-TB or RR-TB (MDR/RR-TB) was relatively flat between 2020 and 2022 (Fig. 15), after a slow downward trend between 2015 and 2019. The estimated number in 2022 was 410 000 (95% UI: 370 000–450 000).2 The reason why the number of people developing MDR/ RR-TB was relatively stable from 2020–2022, in contrast to an estimated rise in the number of people developing TB overall (Fig. 10), is that increases in the overall number of people developing TB have been compensated for by an estimated downward trend (since 2015) in the proportion of people with TB who have MDR/RR-TB, particularly among those with a previous history of treatment (Fig. 16). ”
– Between 1945 and 1965, humans developed several drugs to fight TB, finally making it curable. It was a true achievement of human ingenuity. But we didn’t do a great job of distributing the cure.
#Murray JF, et al. Treatment of Tuberculosis. A Historical Perspective. 2015
https://pubmed.ncbi.nlm.nih.gov/26653188/
Quote: “The antituberculosis benefit of streptomycin was announced in 1945, although application was limited by the rapid development of resistance. para-Aminosalicylic acid, also discovered in 1945, when combined with streptomycin was found to greatly reduce the occurrence of drug resistance. In 1952, isoniazid opened the modern era of treatment; it was inexpensive, well tolerated, and safe. In the early 1960s, ethambutol was shown to be effective and better tolerated than para-aminosalicylic acid, which it replaced. In the 1970s, rifampin found its place as a keystone in the therapy of tuberculosis.”
#WHO. Global Tuberculosis report 2023. 2023
https://iris.who.int/bitstream/handle/10665/373828/9789240083851-eng.pdf?sequence=1
Quote: “Despite the global recovery in 2022, none of the treatment targets set for the period 2018–2022 at the first UN high-level meeting on TB were achieved.”
There are several challenges related to TB treatment that have to do with the long duration of the therapy and the resources available (transportation, time, trained professionals, etc.)
# Dartois, Véronique A., and Eric J. Rubin. Anti-tuberculosis Treatment Strategies and Drug Development: Challenges and Priorities. 2022
https://doi.org/10.1038/s41579-022-00731-y.
Quote: “Because TB is largely a disease that occurs in resource-constrained countries, existing infrastructure only enables moderately complex interventions. This adds substantial operational and implementation challenges to the already daunting research mandate.”
“The shortcomings of TB treatment can be ascribed to four major challenges: curing TB takes considerably longer than any other bacterial infection of the lungs owing to a combination of drug, pathogen and host factors; drug tolerance fuels and synergizes with drug resistance; single drug and regimen development tested in sequence is inherently slow while tools are emerging to rationally prioritize regimens early in the cascade; and a surprisingly small number of drugs have been tested as preventive therapy of LTBI.”
– While Tuberculosis is almost extinct in much of Europe, the US and the Middle East, it is still a very real threat in most of the world. TB kills people primarily in Africa, South America and Asia.
#Dattani, et al. Tuberculosis. 2023
– In 2022 two thirds of all TB cases were in just six countries: India, China, Indonesia, the Philippines, Pakistan and Nigeria. Almost half of all Tuberculosis deaths happened in South East Asia.
#WHO. Global Tuberculosis report 2023. 2023
https://iris.who.int/bitstream/handle/10665/373828/9789240083851-eng.pdf?sequence=1
Quote: “Thirty high TB burden countries accounted for 87% of the world’s TB cases in 2022 and two-thirds of the global total was in eight countries: India (27%), Indonesia (10%), China (7.1%), the Philippines (7.0%), Pakistan (5.7%), Nigeria (4.5%), Bangladesh (3.6%) and the Democratic Republic of the Congo (3.0%).”.
#WHO South-East Asia Region commits to further enhance efforts to end TB, adopt Gandhinagar Declaration. 2023.
Quote: “Home to a quarter of the global population, the WHO South-East Asia Region accounts for nearly half of the new TB cases and deaths globally every year.”
#WHO Global Tuberculosis Report 2023.
Quote: “In 2022, most of the estimated deaths caused by TB among HIV-negative people occurred in the WHO regions of South-East Asia (53%) and Africa (27%), with smaller shares in the Western Pacific (8.5%), the Eastern Mediterranean (7.2%), the Americas (2.1%) and Europe (1.5%); most of the TB deaths among people with HIV occurred in the African Region (68%) (Table 1.2.1)."
Following chart shows the breakdown of the South East Asia region by country.
#OWID. Tuberculosis deaths, 2000 to 2022. Retrieved April 2024.
– But as it is a slow problem like climate change, it was ignored instead of fought aggressively, which enabled more and more strains of TB to develop antibiotic resistance. Which is a problem because we kinda stopped making new drugs.
#WHO. Global Tuberculosis report 2023. 2023
https://iris.who.int/bitstream/handle/10665/373828/9789240083851-eng.pdf?sequence=1
Quote: “Drug-resistant TB continues to be a public health threat. Resistance to rifampicin – the most effective firstline drug – is of greatest concern. TB that is resistant torifampicin and isoniazid is defined as multidrug-resistant TB (MDR-TB). Both MDR-TB and rifampicin-resistant TB (RR-TB) require treatment with second-line drugs."
#Rishi Desai, et al. Mycobacterium tuberculosis (Tuberculosis). 2023
https://www.osmosis.org/learn/Mycobacterium_tuberculosis_(Tuberculosis)
– In the first twentyfive years of the antibiotic era, we developed eight different classes of drugs to treat TB. And then, in the 47 years between 1965 and 2012, we developed none. Developing new drugs is extremely expensive and there was no concentrated effort to eradicate TB, and there simply wasn’t enough profit incentive. There is a vaccine, but it’s over 100 years old and not particularly effective.
Most antibiotic classes used for TB were discovered between 1940 and 1970. From then on, the only new advances were the modification and combination of existing therapies.
#Aminov, Rustam I. A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future. 2010
https://doi.org/10.3389/fmicb.2010.00134
Quote: “The period between the 1950s and 1970s was indeed the golden era of discovery of novel antibiotics classes, with no new classes discovered since then. Therefore, with the decline of the discovery rate, the mainstream approach for the development of new drugs to combat emerging and re-emerging resistance of pathogens to antibiotics has been the modification of existing antibiotics.”
A TB drug was approved in 1998, although it was from the same family as rifamycin, which was approved before.
# Swindells, Susan. New Drugs to Treat Tuberculosis. 2012
Quote: “...the last time a new drug for TB treatment was licensed was 1998 (rifapentine).”
The most remarkable milestones in TB treatment were the development of antibiotics that saved millions of lives. Streptomycin was the first one discovered in 1943. Soon, new treatments needed to be developed and tested because of resistance to the drugs.
#M.D. Iseman Tuberculosis Therapy: past, present and future. 2002
#Al- Humadi et al. Addressing the Challenges of Tuberculosis: A Brief Historical Account. 2017.
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00689/full
Quote: “In 1950s, several anti-TB drugs with different mechanisms of action were discovered and developed, including PAS, isoniazid, pyrazinamide, cycloserine and kanamycin (Figure 1, Table 2). In 1951, streptomycin plus isoniazid were introduced as a TB therapy (Fox et al., 1999), while rifampicin (in 1960) allowed the shortening of TB therapy to 9 months when given with isoniazid, and to 6 months when given with pyrazinamide (American Thoracic Society, 2003). By the 1970s, five antibiotics were available against TB (Figure 1). Afterwards, the MRC TB Unit developed the current short-course therapeutic regimen (isoniazid, rifampicin, pyrazinamide and ethambutol) in collaboration with the United States Public Health Service.”
Investment in TB research averaged just under US$ 1 billion in 2022, less than half of the
US$ 2 billion target set at the first UN high-level meeting on TB for 2018–2022.
#Bloom, Barry R. A Half-century of Research on Tuberculosis: Successes and Challenges. 2023
https://doi.org/10.1084/jem.20230859
Quote: “If one compares public investments in research just for COVID-19 RNA vaccines ($31.9 billion; Lalani et al., 2023) versus all of TB research for 2022 ($1 billion; TAG, 2022), it is clear that lack of funding has been a major impediment to developing new tools to combat TB.”
The BCG vaccine contains weakened bacteria, which means it is not enough to cause the disease but it can activate the immune system against BCG. It is useful in preventing complications from TB, but it is not very effective in providing protection. It is not recommended in countries like the USA, Switzerland and Germany.
#Kaufmann SHE. Vaccine Development Against Tuberculosis Over the Last 140 Years: Failure as Part of Success. 2021
https://pubmed.ncbi.nlm.nih.gov/34691001/
Quote: “The TB vaccine, Bacille Calmette-Guérin (BCG), has saved tens of millions of lives since its deployment. It was the best and only choice available amongst many attempts to develop efficacious vaccines and all competitors, be they subunit vaccines, viable vaccines or killed whole cell vaccines have failed. Yet, BCG is insufficient.”
TB treatments were developed thanks to the collaboration among scientists and private companies.
#Riva, Michele A. From Milk to Rifampicin and Back Again: History of Failures and Successes in the Treatment for Tuberculosis. 2014
https://doi.org/10.1038/ja.2014.108
Quote: “The discovery of new antituberculosis drugs were not related to a single investigator, but to a team of scientist who worked in the same laboratory. The studies and works of the twentieth-century scientists (Sensi, Timbal, Lehmann, Waksman, Schatz, etc.) and their collaboration with private research centers (Lepetit, Ciba, Lederle, Squibb, Bayer, Hoffman-La Roche, etc.) ought to make modern scientific world reflect on how the discovery of new antimicrobial agents can be nowadays threatened by the lack of research in the pharmaceutical industries.”
– But beginning in 2012, we did finally develop two new classes of drugs that treat TB, and we may finally be at an inflection point again, as better vaccines are on the horizon. Companies that made Covid tests also developed a quick test for TB. So, we now have a real opportunity to push this disease back until it dies forever.
The WHO recommended bedaquiline in June 2013 and delamanid in October 2014 for the treatment of some forms of resistant TB in adults. A third drug, pretomanid, was most recently approved by the FDA in 2019 for the treatment of highly drug-resistant forms of TB.
#Perrin, Christophe, et al. Recently Developed Drugs for the Treatment of Drug-resistant Tuberculosis: A Research and Development Case Study. 2022 https://doi.org/10.1136/bmjgh-2021-007490
Quote: “Two drugs with novel mechanisms of action, the diarylquinoline bedaquiline and the nitroimidazole delamanid—as well as pretomanid from the same class of drugs as delamanid—have recently become available to treat drug-resistant tuberculosis (DR-TB) after many decades of little innovation in the field of DR-TB treatment.”
#WHO. New treatment for drug-resistant tuberculosis. 2023
Quote: “Owing to the pressing need for more effective treatment regimens for people with RR-TB and MDR-TB, as well as those with even more extensive patterns of drug resistance, various studies and initiatives to test more effective and novel treatment regimens, including newer and repurposed medicines, have been implemented since the 1990s. … Most recently, new evidence has resulted in a major breakthrough in the treatment that can be recommended for people with MDR/RR-TB and pre-XDR-TB. …The key change in the latest WHO recommendations is the addition and prioritization of a new all-oral 6-month regimen. For people with MDR/RR-TB, the regimen comprises bedaquiline (B), pretomanid (Pa), linezolid (L) and moxifloxacin (M), and is referred to as BPaLM; for people who have pre-XDR-TB, the regimen can be used without moxifloxacin (BPaL)”
#Chakraborty, Sumit, and Kyu Y. Rhee. Tuberculosis Drug Development: History and Evolution of the Mechanism-Based Paradigm. 2015 https://doi.org/10.1101/cshperspect.a021147.
Quote: “Bedaquiline (BDQ). Apart from being the only clinical drug to be approved for the treatment of TB in >40 yr, bedaquiline (BDQ) (previously known as TMC207 and R207910) is also the first FDA-approved drug to have been developed in the modern era of molecular sciences.”
#Bloom, Barry R. A Half-century of Research on Tuberculosis: Successes and Challenges. 2023
https://doi.org/10.1084/jem.20230859
Quote: “The challenge remains whether a safe vaccine as effective as natural Mtb infection can be created that will be >50% effective in all countries. While there are currently 176 trials of COVID-19 vaccines (WHO, 2023), in September 2022, there were only 16 TB vaccine candidates in clinical trials: four in Phase I, eight in Phase II, and four in Phase III.”
“New, safe vaccines more effective than BCG are being developed, but still, only three new candidates are in Phase 3 trials.”
#Kaufmann SHE. Vaccine Development Against Tuberculosis Over the Last 140 Years: Failure as Part of Success. 2021
https://pubmed.ncbi.nlm.nih.gov/34691001/
Quote: “The last decades have witnessed a reawakening of novel vaccine approaches based on deeper insights into immunity underlying TB and BCG immunization. In addition, technical advances in molecular genetics and the design of viral vectors and adjuvants have facilitated TB vaccine development.”
#Martini, M., et al. Tuberculosis: An Ancient Disease that Remains a Medical, Social, Economical and Ethical Issue 2020
https://doi.org/10.15167/2421-4248/jpmh2020.61.1s1.1475
Quote: “Vaccines are important in the prevention and control of tuberculosis, but the only now available preventive vaccine against TB, bacilli Calmette-Guérin (BCG), is not effective for prevention of pulmonary TB. For this reason, it is very important to develop new vaccines for TB prevention and control in adults. Around 14 TB vaccine candidates are in this moment in clinical evaluation, they can be classified into two groups including preventive pre- and post-exposure vaccines: subunit vaccines, and whole-cell vaccines.”
There are also ongoing clinical trials for drugs with new mechanisms:
#Dawson et al. A 4-Month Regimen of Quabodepistat, Delamanid, and Bedaquiline for Pulmonary TB: Interim Results. 2024.
Quote: “This interim analysis of the phase 2b/c, randomized trial (NCT05221502) evaluates the safety, efficacy, and pharmacokinetics of QBS in combination with DLM and BDQ for 4 months in participants with DS-TB compared to 6-month RHEZ treatment. Participants were randomized (1:2:2:1; stratified by chest x-ray bilateral cavitation and HIV status) to once-daily QBS 10 mg, 30 mg, or 90 mg in combination with DLM and BDQ, or RHEZ. The follow-up period (to 52 weeks post-randomization) is ongoing. The primary endpoint was proportion of participants achieving sputum culture conversion (SCC) by the end of the treatment period. Here, we report interim results after 117/122 (96%) randomized participants completed study treatment.”
– A century ago in the United States, there were almost as many hospital beds for TB patients as for treating all other illnesses and injuries combined. The white death was a leading cause of death in the US and then one day it just wasn’t anymore. And we can do this again.
#Gerald N Grob. Living in the Shadow of Death: Tuberculosis and the Social Experience of Illness in American History. Sheila M. Rothman. 1994.
#Historical Statistics of the United States, 1789 - 1945. Retrieved March 2024.
#John Elflein. Major causes of death in the U.S.: 1900 and 2021. 2023
#Anya Grahn. Tuberculosis Sanitariums: Reminders of the White Plague.2015
https://savingplaces.org/stories/tuberculosis-sanitariums-reminders-of-the-white-plaque
Quote: “In the 1920s and '30s, states began passing laws that required state hospitals to provide beds equal to the number of tuberculosis-related deaths in each region.”
#CDC. Achievements in Public Health, 1900-1999: Control of Infectious Diseases.1999
https://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm
Quote: “In 1900, the three leading causes of death were pneumonia, tuberculosis (TB), and diarrhea and enteritis, which (together with diphtheria) caused one third of all deaths. In 1997, heart disease and cancers accounted for 54.7% of all deaths, with 4.5% attributable to pneumonia, influenza, and human immunodeficiency virus (HIV) infection ”
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