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Increased chronic diseases in animals because of environmental changesEpithelial barrier dysfunction and associated diseases in companion animals: Differences and similarities between humans and animals and research needs• Pets share our environment and are regarded by many as beloved family members. Some reside in gardens, while others live within our homes, even sharing our sleeping spaces.• The modern world has introduced more than 350,000 new chemicals into our daily lives, many of which become part of the life of domestic animals. Cleaning products, food additives and air pollutants have a major impact on the health of animals.• Pets are more frequently exposed to disinfectants, shampoos and household cleaning materials. They spend much time lying on the floor, walking barefoot on surfaces, and licking themselves. Pets, being closer to ground level, are also more likely to be affected by environmental pollutants such as dust and residues from cleaning products.• Substances harmful to humans are subsequently banned, however they are often continued tobe used in pet products.• The huge amounts of microplastic entering the lives of all living things in the world, substantially affect animals. Toys, grooming and hygiene products, and food and water bowls have become essential items for many pet owners. Many of these products contain significant amounts of plastic, which can degrade into micro- and nanoplastic particles that pose major risks to the health of animals.•As observed in humans, packaged and processed modern food of animals contain several additives and emulsifiers that show toxicity to their gastrointestinal system.• As environmental conditions continue to change, further research is needed into how these changes affect animal health.• The “Epithelial Barrier Theory” suggests that the growing prevalence of allergic, autoimmune, and other chronic conditions is rooted in increased exposure to agents that compromise the integrity of epithelial barriers. This increased exposure is primarily associated with factors linked to industrialization, urbanization, and the pressures of modern life, including pollution, dietary changes, stress, and widespread use of cleaning products, chemicals and antibiotics. As a result, various harmful substances, including toxins, allergens, and pathogens, can cross these weakened barriers more easily, interacting with the immune system and cause allergic, autoimmune, and neuropsychiatric diseases—all of which have become more prevalent in recent decades.• The epithelial barrier theory brings attention to the hidden dangers that threaten the health of both humans and animals. Negative impacts on the environment inevitably affect human and animal health, reflecting the core idea behind the One Health concept.Link for free download: doi.org/10.1111/all.16343Correspondence: Prof. Dr. Cezmi A. Akdis, MDDirector Swiss Institute for Allergy and Asthma Research (SIAF) Herman-Burchard-Strasse 9CH-7265 Davos WolfgangPhone: +41 81 410 08 48e-mail: akdisac@siaf.uzh.ch
Epithelial barrier theory-related diseases, microbial dysbiosis and inflammation- To explain the growing prevalence of allergic, autoimmune and neuropsychiatric diseases, the epithelial barrier theory is a central focus of worldwide opinion leaders.- According to the epithelial barrier theory, exposure to environmental toxic substances in humans and animals damages the epithelium, the layer of cells that covers the surface of our skin, digestive tract, lungs, and eyes. Epithelial barrier dysfunction is induced by together with microbial dysbiosis, immune system activation, along with the development of inflammation in the tissues. - Together with worldwide opinion leaders, we identified 68 epithelial barrier-related diseases, including skin diseases, airway diseases, digestive tract diseases, neuropsychiatric diseases, autoimmune, autoinflammatory and metabolic diseases, ocular diseases. - These diseases associated with the epithelial barrier theory share common features, such as increased prevalence after the 1960s or 2000s with the same method of diagnosis, microbial dysbiosis with decreased commensals and increased opportunistic pathogens, immune system activation and inflammation in the affected tissues as well as in the circulation. - In 1960s these diseases were affecting 20-30 million humans which increased by 100 times to 2 billion patients. The world’s population increased by 2 times in the meantime. - With the contribution of 48 international opinion leaders and 642 references this immense study shows the evidence and similarities in the epidemiology, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation in 68 diseases that substantially affect the human health. - The immense increase in the prevalence of these diseases caused a huge healthcare burden consuming more than 10% of the GDP of every country for health care. The increased socioeconomic burden made the healthcare sector the main locomotive of the world’s economy. - The onset and exacerbations of these diseases is attributed to a damaged epithelial barrier and inflammation triggered by hazardous substances originating from industrialization, urbanization and westernized lifestyles, such as air pollution, microplastics, nanoplastics, several surfactant formulations in detergents, household cleaners, dishwashers, hand sanitizers, disinfectants, toothpastes, and processed food emulsifiers and additives. Epithelial barrier damaging agents initiate the crosstalk between the epithelial barrier, microbiota, and an immune response, as reported in numerous studies on the pathogenesis of epithelial barrier-associated diseases. - The studies presented within our research emphasize the significant implications of the epithelial barrier theory in unraveling the pathogenesis of chronic non-communicable diseases and to elucidate novel strategies for the development of preventive or therapeutic approaches. Correspondence: Prof. Dr. Cezmi A. Akdis, MDDirector Swiss Institute for Allergy and Asthma Research (SIAF) Herman-Burchard-Strasse 9CH-7265 Davos WolfgangPhone: +41 81 410 08 48
The health of athletes and physically active people is in the focus of the current research in the Swiss Institute of Allergy and Asthma Research (SIAF) in collaboration with the Sports Medicine Department of the Davos Hospital (Swiss Research Institute for Sports Medicine – SRISM) on the effects of environmental pollutants and nutrition on the barrier function of the skin, respiratory tract and digestive tract. Epithelial barrier defects play a crucial role in defense against external influences such as viruses, bacteria, allergens and environmental pollutants. An intact barrier function is therefore essential for health and well-being.While modern living conditions expose us to a variety of toxic and harmful substances, athletes are faced with particular challenges due to their increased risk of exposure to these substances. Various cleaning products, air pollutants, small plastic particles (micro and nanoplastic) and food additives can damage the barrier function of skin and mucous membranes, which can lead to a disturbed composition of the microbiome (skin and intestinal bacterial flora) and chronic inflammatory reactions.The situation is particularly challenging for top athletes. The cumulative exposure to environmental toxins, cleaning agents, high levels of air pollution and special nutritional conditions can affect their overall health and sports performance. Reduced resistance to infection; increased hygiene conditions; increased burden of air pollution affect the health and performance of the athletes depending on their intensity of exercise, type of indoor, outdoor and water sports. Despite the well-known health benefits of physical activity, athletes must therefore also pay attention to a healthy diet and the protection of their epithelial barriers and healthy microbiome in order to minimize long-term health consequences and keep up with their top performance.In addition, our studies reviewed here demonstrate how food preferences, in particular the consumption of processed foods, can impair the epithelial barrier function. The use of emulsifiers and other additives in sports nutrition can lead to a disruption of the epithelial barriers and microbiome, which is associated with an increased risk of several diseases, such as allergies, autoimmunity and neuropsychiatric conditions.Together these novel concepts highlight a holistic approach to overall health and physical performance of athletes, linked with their nutrition and exposure to pollution and toxic substances affecting the integrity of their barriers of skin and mucosal body surfaces and healthy microbiome.Link for free download: http://doi.org/10.1111/all.16221 Correspondence:Prof. Dr. Cezmi A. Akdis, MDDirectorSwiss Institute for Allergy and Asthma Research (SIAF) Herman-Burchard-Strasse 9CH-7265 Davos WolfgangPhone: +41 81 410 08 48e-mail: akdisac@siaf.uzh.ch Dr. Walter KistlerHead of Department, Davos Sports & HealthSpital Davos AGPromenade 4CH-7270 Davos PlatzPhone: +41 81 414 84 84 e-mail: wkistler@spitaldavos.chWeb:https://www.siaf.uzh.chhttps://sportsmed-research.ch/https://www.davossportshealth.ch
Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper published in AllergyThe revision of the current allergic disease nomenclature based on symptoms and organ dysfunction has been long-awaited at the time of modern patient-tailored treatments and precision medicine. The new classification is based on disease mechanisms, thus facilitating targeted and personalised disease management.EAACI is the world leader in allergy science and education. The world’s key opinion leaders gathered around the initiative of the European Academy of Allergy and Clinical Immunology (EAACI) to present a new classification of allergic disorders based on the mechanisms of diseases. Published online today in Allergy, the position paper reveals the new way allergic diseases are perceived.We expect the new classification to profoundly change the healthcare professionals’ approach to managing allergic diseases since it provides key solutions to a personalised approach. It is focused on the roles of immune-competent cells, changes in the tissues, the role of microbial infections, and genetic and epigenetic influences, all affecting the protective epithelial barrier of the skin, respiratory tract and gut.The exponential growth of precision diagnostic tools, including omic technology, molecular diagnostics, imaging, sophisticated genetic and epigenetic editing, nano-technologies, etc., compels us to introduce a more nuanced concept, moving the field towards precision and personalised medicine. The general consensus and fast dissemination of the new nomenclature of allergic diseases are crucial to developing the entire field of management of immune-mediated diseases.The cultural change brought by the new nomenclature will lead to novel concepts of diagnostic tools, improving therapies, and disease management and will guide future research into more innovative strategies for patient care. This will include new pinpoint targeted immune-based therapies, especially with substances made from living organisms, called biologicals, allergen immunotherapy, as well as strategies to alter the composition of the microbiome in humans among many others. The value of an idea lies in the use of it. We hope that the new nomenclature for allergic diseases developed by EAACI will help healthcare professionals and patients find a better way to manage and even cure allergic diseases.Direct link to download free access article: https://onlinelibrary.wiley.com/doi/10.1111/all.15889Correspondence: Prof. Dr. Cezmi A. Akdis, MDDirector Swiss Institute for Allergy and Asthma Research (SIAF) Herman-Burchard-Strasse 9CH-7265 Davos WolfgangPhone: +41 81 410 08 48
The results underscore the pressing need to establish a new safety standard for household cleaning productsThe Swiss Institute of Allergy and Asthma Research (SIAF) today announced the findings of a new study demonstrating the mechanisms of skin epithelial barrier impairment caused by household laundry detergents. Published online today in Allergy, Household laundry detergents disrupt barrier integrity and induce inflammation in mouse and human skin, by Rinaldi et al., the research reveals the detrimental effects of widely-used laundry detergents and sodium lauryl (dodecyl) sulphate (SDS) on skin epithelial integrity and inflammation –– even at the significantly low concentrations that we are exposed to in our daily life.The study comes from the epithelial biology research group at SIAF, associated with the University of Zurich, which has been working on epithelial barriers and environmental substances for more than 20 years. A new method has been developed to measure the damage to the skin barrier integrity induced by exposure to household laundry detergents and SDS in a few seconds by using electrical impedance spectroscopy. The continuous use of household cleaning products can impair the protective cellular linings of the skin, respiratory tract, and gut, known as the epithelial barriers. This impairment can lead to microbial dysbiosis, bacterial migration, chronic inflammation, and immune dysfunction. The Epithelial Barrier Theory proposes that modern society’s dependence on barrier-damaging agents — which include surfactants, preservatives, emulsifiers, microplastics and other chemicals— is responsible for the global, epidemic-level rise in chronic diseases observed during the last 65 years.Household laundry detergents and sodium lauryl (dodecyl) sulfate damage skin epithelial cellsAn impaired epithelial barrier function has been implicated in various skin and respiratory allergies, metabolic and autoimmune disorders, such as asthma, allergies, dermatitis, colitis, diabetes, hepatitis, and obesity. The prevalence of these diseases has markedly increased in Western culture since the 1960s along with industrialization and modernization. SDS is one of the most commonly used anionic surfactants in household cleaners, dishwasher detergents, and even in toothpaste. Nevertheless, there is no international standardization for the dose of these toxic substances. SDS was first introduced in the mid-20th century in commercial laundry detergents as a surfactant, and it is now found in a wide range of cleaning products at a range from 5-20% SDS.The research revealed that highly diluted household laundry detergents and SDS damage the skin epithelial barrier by using mouse models and biostabilized natural human skin (NativeSkin®, in collaboration with Genoskin, https://genoskin.com/). This barrier disruption was induced by damage, stress and inflammatory responses in epithelial cells. The study highlights that these effects were observed at doses significantly lower than those recommended for handwashing and those present in the residual laundry liquid after rinsing.An Electrical Impedance Spectroscopy (EIS) tool (Nevisense®, in collaboration with Scibase, https://scibase.com/) was used in the study to detect skin barrier dysfunction/impairment. The device acquires skin barrier measurements within only seconds and is currently available for clinical use in diagnosing melanoma and studying inflammatory skin conditions. Exciting research is ongoing in this context for the early prediction of infantile eczema development in babies, patient follow-up and response of patients to various dermatitis treatments.Link to the article for further reading (open for free download): https://doi.org/10.1111/all.15891Correspondence: Dr. Yasutaka Mitamura, Principal Investigator, Swiss Institute of Allergy and Asthma Research, Davos, SwitzerlandProf. Dr. Cezmi A. Akdis, Director, Swiss Institute of Allergy and Asthma Research, Davos, Switzerland
Polysorbate 20 and Polysorbate 80 were shown to damage the gut barrier, leading to cell death and inflammation –– even at doses 10 to 20 times lower than those currently authorized for useThe findings illustrate the urgent need to use fine-scale immunology to evaluate safety and establish a new standard for consumer products
The Swiss Institute of Allergy and Asthma Research (SIAF) today announced the findings of a new study demonstrating the mechanisms of gut epithelial barrier impairment caused by food emulsifiers. Published today in Allergy, the research reveals the detrimental effects of the widely-used emulsifiers Polysorbate 20 (P20) and Polysorbate 80 (P80) on intestinal epithelial integrity and inflammation –– even at significantly lower concentrations than those currently authorized.The study comes from the research group of epithelial biology at SIAF, associated with the University of Zurich, which has been working on epithelial barriers for more than 20 years.Compounds found in everyday consumer products — such as processed foods, detergents, household cleaners, and cosmetics — can impair the protective cellular linings of the skin, respiratory tract, and gut known as the epithelial barriers. This impairment can lead to microbial dysbiosis, bacterial migration, chronic microinflammation, and immune dysfunction. The Epithelial Barrier Theory proposes that modern society’s reliance on these barrier-damaging agents — which include preservatives, emulsifiers, surfactants, and microplastics — is responsible for the global, epidemic-level rise in chronic health conditions over the last 65 years.Polysorbate 20 and polysorbate 80 damage gastrointestinal epithelial cellsPolysorbates are a type of nonionic surfactant often used in food preparation to improve the texture and consistency of foods, as well as to act as an emulsifier to help mix ingredients that might not otherwise blend well, such as oil and water. They were first introduced in the mid-20th century as a food additive, and their use has since become widespread globally. Today, they are found in a wide range of processed foods, including ice cream, baked goods, salad dressings, and sauces, at concentrations up to 1%.The research group investigated the impact of P20 and P80, the most common types of polysorbates used in foods, on epithelial barriers and inflammatory response. Using human models, such as induced pluripotent stem cell-derived human intestinal organoids, colon organoids, organ-on-a-chips, and liquid-liquid interface cultures, the researchers revealed that P20 and P80 damage the gut barrier. This disruption is due to cell death and molecular toxicity, as well as the triggering of numerous genes and proteins that stimulate inflammatory responses in epithelial cells (known as ‘epithelitis’). The food emulsifiers also triggered a range of cellular processes, including tissue damage, alterations in cell signaling and communication, and induced inflammation.The study highlights that these effects occurred even at doses much lower than those approved for public use.Further, P20 was found to have significant interaction with the ferroptosis pathway – a form of regulated cell death – and influences immune response and energy production. P80, on the other hand, impacted lipid metabolism, the aryl hydrocarbon receptor pathway (involved in detecting and responding to environmental toxins), cellular aging, and immune responses.Considering that a defective epithelial barrier can facilitate the entry of allergens and induce an inflammatory response that can initiate or aggravate many chronic inflammatory diseases, the need to further evaluate the health hazards of these barrier-damaging compounds –– and the search for safer alternatives –– is all the more urgent.Link to the article for further reading (open for free download): https://doi.org/10.1111/all.15825
According to the epithelial barrier theory, disruption of epithelial barriers by environmental and toxic agents triggers microbial dysbiosis, bacterial translocation to subepithelial areas and local or systemic immune/inflammatory response to environmental agents, allergens and microbes. Such events have been implicated in the development of chronic conditions like allergic, autoimmune, and metabolic diseases. In severe cases of COVID-19, characteristic features include hyperinflammation, hyperactivated immune responses (referred to as the cytokine storm), cellular infiltration, and organ damage.Biomarkers of intact or defective epithelial barriers are associated with disease severityThe compromised epithelial barrier facilitates the translocation of microbiota and their secreted metabolites, thus initiating or exacerbating inflammatory cascades in many inflammatory diseases. The research group of epithelial biology in the Swiss Institute of Allergy and Asthma Research, which is associated with the University of the Zurich, has been working on epithelial barriers for more than 20 years. Today they have published a study in Allergy, Journal of the European Academy of Allergy and Clinical Immunology providing substantial evidence that epithelial barrier function is compromised in particularly severe COVID-19 patients, which is also in line with the epithelial barrier theory. The authors analyzed the amount of bacterial DNA leakage to circulation and showed the link between disrupted epithelial barriers and an excessive inflammatory response. They identified other major inflammatory proteins, AREG, AXIN1, CLEC4C, CXCL10, CXCL11 and TRANCE correlated strongly with bacterial translocation and can be used to predict and discriminate severe COVID-19 cases from healthy controls and mild cases. Interestingly all of these analyses were done at the time of hospital admission even before severe symptoms occurred demonstrating that there is a link between certain protein biomarkers and disease progression from moderate to severe COVID-19 and death. These findings emphasize the value of early detection of biomarkers of epithelial barrier leakiness and bacterial translocation as indicators of poor disease outcome. They have implications on other infections, chronic diseases and may change the daily clinical practice and facilitate early therapeutic interventions.Free Access Link to the article for further reading: http://doi.org/10.1111/all.15800Correspondence: Ismail Ogulur, Cezmi A. AkdisE-mails : ismail.ogulur@siaf.uzh.ch, cezmi.akdis@siaf.uzh.ch
Residue from rinse agents is left behind on dishes after they are cleaned in professional-grade dishwashers. This damages the natural protective layer in the gut and can contribute to the onset of chronic diseases, as demonstrated by researchers working with organoids at the Swiss Institute of Allergy and Asthma Research, an associated UZH institute.Whether it’s at a restaurant, at school or in the barracks, commercial dishwashers help plates, glasses and cutlery become squeaky clean and dry in a matter of minutes. These practical appliances come with risks, however, as was recently discovered in a new study by researchers at the Swiss Institute of Allergy and Asthma Research (SIAF), an associated institute of the University of Zurich (UZH). One ingredient in particular found in commercial rinse agents has a toxic effect on the gastrointestinal tract.Chemical residue on clean platesA typical cycle in a commercial dishwasher involves circulating hot water and detergent for around 60 seconds at high pressure. Afterwards, there is a second 60-second washing and drying cycle in which water and a rinse agent are applied. “What’s especially alarming is that in many appliances, there’s no additional wash cycle to remove the remaining rinse aid,” says Cezmi Akdis, UZH professor of experimental allergology and immunology and director of the SIAF, who led the study. “This means that potentially toxic substances remain on the dishes, where they then dry in place.” When the dishes are used the next time, this dried chemical residue can easily end up in the gastrointestinal tract.This inspired the research team under Akdis to investigate what effect the components of commercial-grade detergents and rinse agents have on the epithelial barrier in the gut – the layer of cells that lines the intestinal tract and controls what enters the body. A defect in this barrier is associated with conditions such as food allergies, gastritis, diabetes, obesity, cirrhosis of the liver, rheumatoid arthritis, multiple sclerosis, autism spectrum disorders, chronic depression and Alzheimer’s disease.Similar protective layers are also present on the skin and in the lungs. As numerous studies have shown, many additives and chemicals that we encounter in everyday life can damage these layers. “We assume that defective epithelial barriers play a role in triggering the onset of two billion chronic illnesses,” says Akdis. This connection is explained by the epithelial barrier hypothesis, which Akdis has helped develop during his more than 20 years of research in this field.Toxic substance in rinse agentsThe researchers used a newly developed technology for their study – human intestinal organoids and intestinal cells on microchips. The tissue forms a three-dimensional clump of cells that is very similar to the intestinal epithelium in humans. The team used various biomolecular methods to analyze the effect that commercial detergents and rinse aids have on these cells. They diluted these substances to reflect the amounts that would be present on dry dishes (1:10,000 to 1:40,000).The result was that high doses of rinse agents killed the intestinal epithelial cells and lower doses made it more permeable. Researchers also observed the activation of several genes and cell signaling proteins that could trigger inflammatory responses. A more detailed analysis showed that one component of the rinse agent – alcohol ethoxylates – was responsible for this reaction.According to Akdis, these findings have significant implications for public health. “The effect that we found could mark the beginning of the destruction of the gut’s epithelial layer and trigger the onset of many chronic diseases,” he says. Akdis calls for an immediate response: “It is important to inform the public about this risk, since alcohol ethoxylates seem to be commonly used in commercial dishwashers.”Literature:Ismail Ogulur, Yagiz Pat, Tamer Aydin, Duygu Yazici, Beate Rückert, Yaqi Penq, Juno Kim, Urszula Radzikowska, Patrick Westermann, Milena Sokolowska, Raja Dhir, Mubeccel Akdis, Kari Nadeau, Cezmi A. Akdis. Gut epithelial barrier damage caused by dishwasher detergents and rinse aids. The Journal of Allergy and Clinical Immunology. 1 December 2022. DOI: 10.1016/j.jaci.2022.10.020
Humans are exposed to a variety of toxins and chemicals every day. According to the epithelial barrier hypothesis, exposure to many of these substances damages the epithelium, the thin layer of cells that covers the surface of our skin, lungs and intestine. Defective epithelial barriers have been linked to a rise in almost two billion allergic, autoimmune, neurodegenerative and psychiatric diseases.Epithelial cells form the covering of most internal and external surfaces of the human body. This protective layer acts as a defense against invaders – including bacteria, viruses, environmental toxins, pollutants and allergens. If the skin and mucosal barriers are damaged or leaky, foreign agents such as bacteria can enter into the tissue and cause local, often chronic inflammation. This has both direct and indirect consequences.Chronic diseases due to defective epithelial barriersCezmi Akdis, Director of the Swiss Institute of Allergy and Asthma Research (SIAF), which is associated with the University of Zurich (UZH), has now published a comprehensive summary of the research on epithelial barrier damage in Nature Reviews Immunology. “The epithelial barrier hypothesis proposes that damages to the epithelial barrier are responsible for up to two billion chronic, non-infectious diseases,” Professor Akdis says. In the past 20 years, researchers at the SIAF alone published more than 60 articles on how various substances damage the epithelial cells of a number of organs.Rise in allergic and autoimmune conditionsThe epithelial barrier hypothesis provides an explanation as to why allergies and autoimmune diseases have been increasing for decades – they are linked to industrialization, urbanization and westernized lifestyle. Today many people are exposed to a wide range of toxins, such as ozone, nanoparticles, microplastics, household cleaning agents, pesticides, enzymes, emulsifiers, fine dust, exhaust fumes, cigarette smoke and countless chemicals in the air, food and water. “Next to global warming and viral pandemics such as COVID-19, these harmful substances represent one of the greatest threats to humankind,” emphasizes Akdis.Asthma, Alzheimer’s et al.Local epithelial damage to the skin and mucosal barriers lead to allergic conditions, inflammatory bowel disorders and celiac disease. But disruptions to the epithelial barrier can also be linked to many other diseases that are characterized by changes in the microbiome. Either the immune system erroneously attacks “good” bacteria in healthy bodies or it targets pathogenic – i.e. “bad” – invaders. In the gut, leaky epithelial barriers and microbial imbalance contribute to the onset or development of chronic autoimmune and metabolic diseases such as diabetes, obesity, rheumatoid arthritis, multiple sclerosis or ankylosing spondylitis. Moreover, defective epithelial barriers have also been linked to neurodegenerative and psychiatric diseases such as Parkinson’s disease, Alzheimer’s disease, autism spectrum disorders and chronic depression, which may be triggered or aggravated by distant inflammatory responses and changes in the gut’s microbiome.Prevention, intervention – and more research“There is a great need to continue research into the epithelial barrier to advance our understanding of molecular mechanisms and develop new approaches for prevention, early intervention and therapy,” says Akdis. Novel therapeutic approaches could focus on strengthening tissue-specific barriers, blocking bacteria or avoiding colonization by pathogens. Other strategies to reduce diseases may involve the microbiome, for example through targeted dietary measures. Last but not least, the focus must also be on avoiding and reducing exposure to harmful substances and developing fewer toxic products.Literature: Cezmi A. Akdis. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nature Reviews Immunology. 12 April 2021. DOI: 10.1038/s41577-021-00538-7
