FUNGAL INFECTIONS (MYCOSES)

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MYCOSES

Mycoses are infections caused by pathogenic fungi. And they include superficial mycoses, cutaneous mycoses, subcutaneous mycoses, systemic or deep-seated mycosis and opportunistic mycoses. The name given to the different types of mycoses or fungal infections in humans usually depends on the affected tissue or parts of the body where the infecting or invading pathogenic fungi is localized in the body. However, other forms of fungal infections which are not directly caused by pathogenic fungi but their toxic products and the untoward reactions which they provoke in the affected host also exist. Such clinical conditions include mycotoxicoses and fungal allergies. Mycotoxicoses and fungal allergies are pathological conditions of some fungi, which are usually initiated following human contact with fungal spores and their toxins especially by eating food containing fungal mycotoxins or exotoxins from toxin-producing fungi.

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Mycotoxicoses are caused by mycotoxins (fungal exotoxins) produced by some fungal organisms that infest food especially cereals and grains that are poorly stored. It can also occur through the inhalation of fungal spores from the environment. Human mycotoxicoses are usually caused through the consumption of foods containing mycotoxins especially those of Aspergillus flavus. A. flavus is known to produce aflatoxins in food. Mycotoxins are produced in food on which the pathogenic fungus is growing, and the consumption of such fungus-toxin infested food leads to mycotoxicoses, a clinical condition similar to the actions of bacterial toxins. Apart from causing fungal disease, mycotoxicoses causes loss of revenue in the agricultural sector and the gross-domestic product (GDP) of agricultural-producing nations. It can also cause the rejection of mycotoxin-infested food products; increase the prices of food commodity in the market, cause food scarcity and other economic consequences in places where they occur.

Fungal spores are ubiquitously found in the environment; and their inhalation by individuals who are allergic to them can cause fungal allergies or hypersensitivity reactions. Most fungal allergies are occupational diseases and they mostly occur in people who always come in contact with fungal spores such as farmers and those that work in forests or places where fungal spores are constantly retained in dust particles as aerosols. Construction workers and builders may also be affected through the inhalation of fungal spores resulting from aerosolized dust particles containing infectious fungi. Asthma is a common example of the hypersensitivity reaction that follows the inhalation of potent fungal spores. Most fungal infections are occupationally-related i.e., they occur in people who work in a certain type of job such as construction workers, farmers, builders, forest workers and workers who are constantly exposed to dust and soil particles as aforementioned.

Other predisposing factors to fungal infection include the use of indwelling medical devices (for example, urine catheters and respirators), previous organ/tissue transplant, use of immunosuppressive drugs, prolonged antibiotic usage (which depletes the normal bacterial flora that prevent the overgrowth of fungi that are mycoflora in the body), age of the individual (the elderly with depleting immunity and infants or children whose immune system are still developing are more prone to fungal infections) and other underlying disease conditions (for example, HIV/AIDS and cancer) which impairs the host immune system.

In terms of age factor, the elderly and newborns are more prone to some fungal infections because the immune system of these individuals is either decreasing (as seen in the elderly) or is being developed (as seen in neonates). Nevertheless, there are lesser fungal infections than bacterial related diseases because of the body’s natural resistance to fungal invasion. Most fungal infections (for example, cryptococcosis, aspergillosis and systemic candidiasis) are opportunistic diseases; and they mainly occur in people whose immune system has been compromised as aforementioned. Both the innate and acquired immunity of an individual plays vital roles in the prevention and containment of fungal infection in the body of a human host. Based on their portal of entry (such as nose, skin and eye), the type of infected tissue and the site of attack or infection, fungal mycoses are generally classified as superficial mycoses, cutaneous mycoses, subcutaneous mycoses, systemic mycoses and opportunistic mycoses (Figure 1).

Figure 1. Illustration of mycoses in the human body. The diagram illustrates the different organs and body sites that are attacked or invaded by pathogenic fungi. Cutaneous mycoses affect the hair, nails and within the skin; subcutaneous mycoses affects the skin surface, nails and hair while subcutaneous mycoses affects the underneath of the skin layer. Photo courtesy: https://www.microbiologyclass.com

The intact skin is the main barrier or biological boundary line between the human body and the outside environment. It protects the internal body environment from the entry of pathogenic microorganisms and from other external harmful activities. The skin regulates the body’s temperature, and it helps in the synthesis of vitamin D in humans. The skin excretes nitrogenous wastes and CO2 through the excretion of sweat; and it also control environmental factors that affect deeper tissues of the body. The skin is the tissue that covers the outside surface of the body; and it is also the site for the synthesis of vitamin D especially when exposed to sunlight. The human skin is the largest organ in the human body; and it is mainly made up of two main layers which are the epidermis and dermis aside other associated parts and cells (Figure 2).

Figure 2. Illustration of the cross-section of human skin. The skin carries out a variety of functions in the body of vertebrates inclusive of humans. And it is a major site for the occurrence of superficial mycoses in humans. Photo courtesy: https://www.microbiologyclass.com

SUPERFICIAL MYCOSES

Superficial mycoses are fungal infections which are only limited to the keratinized outer layer of the skin, hair and nails. They also affect the hair shaft. Superficial mycoses unlike other forms of mycoses rarely result in inflammatory reactions in the host but it is usually characterized by intense itching and peeling or scaling of the affected body site(s) especially the outer skin surface. They are self-limiting mycoses and benign in their action. Superficial mycoses are non-systemic fungal infections that only infect the surface layer of the skin, and they are usually associated to or caused by poor personal or environmental hygiene. Fungal organisms that cause superficial mycoses are the least known penetrating or invasive fungal species that cause mycoses in humans (Table 1). This is because they only colonize the keratinized outer layer of the skin especially the malpighian layer of the epidermis – which contains keratinocytes that produces the protein keratin (Figure 2). Superficial mycoses generally have no systemic or invasive effect on the body during or after prior infection with the causative agents.

Table 1. Synopsis of superficial mycoses

Superficial mycoses are contagious mycoses, and thus it can be transferred or spread in a defined human population through direct body contact with infected persons. People who share personal items of infected individuals such as bathing soap and towels or bed sheaths are at risk of catching or contracting superficial mycoses. Though most superficial mycoses are self-limiting and can heal on their own even without formal treatment, they can best be treated through a careful removal of the affected scalp of the skin or infected hairs and nails. Medical intervention is also required for proper treatment and management of superficial mycoses. Subcutaneous mycosis is common amongst children, adolescents and young people who may occasionally experience some level of poor personal hygiene in their lifetime especially during their early years of development. However, the disease is normally localized or endemic in underdeveloped or developing countries especially in places where personal and public hygiene is poor; and both children and adults are easily infected. Topical antifungal agents can be applied in some cases to hasten the healing process of the infection and thus inhibit fungal growth and spread in the affected body sites. Nevertheless, proper personal and environmental hygiene is required to control superficial mycoses or infection with causative organisms of superficial mycoses.

CUTANEOUS MYCOSES

Cutaneous mycoses are fungal infections of the skin, nails and hairs; and they are mainly caused by dermatophytes. While superficial mycoses involves the outermost layers of the skin; cutaneous mycoses generally affects the epidermis layer of the skin i.e., the layer of the skin that underlies the outer skin surface (Figure 2). Cutaneous mycoses can also be called dermatophytoses or dermatomycoses since they are caused by dermatophytes. Dermatophytes arefungi that can degrade the keratinized tissues of living organisms including those of humans and animals. They are fungal organisms that cause fungal infection or diseases of the skin. As earlier said, the outer layer of the human skin is rich in keratin. Keratin is an insoluble protein molecule produced by keratinocytes and commonly found in hairs, nails and skin scrapings including the feathers and hairs of other animals. Dermatophytes are moulds that mainly attack the non-living or dead keratinized tissues of the human and animal skin. Some of the notable infections caused by dermatophytes in humans include athlete’s foot, jock itch and ringworm or Tinea.

Dermatophytes are moulds that cause cutaneous fungal infections in humans. And even though they may have the ability to penetrate or invade keratinized tissues of the skin, hair or nails; dermatophyte infection in humans are generally restricted to the nonliving cornified region of the epidermis that is closer to the outside environment. Ringworm or Tinea is a communicable fungal infection very common amongst young children and adolescents (Figure 3).

Figure 3. Illustration of dermatophytoses (Ringworm) on the skin. A. Ringworm (Tinea) is caused by a fungal infection on the skin; and the infection is characterized by the formation of an erythematous scaling on the affected part of the skin (arrow). The phrase ‘erythematous’ is from erythema, which means redness of the skin or mucous membrane. B. Bright field micrograph of Microsporum species, one of the causative agents of ringworm infection (dermatophytoses). Photo courtesy: https://www.microbiologyclass.com

Adults are less susceptible to ringworm infection due to the fungistatic action of fatty acids in the sebum produced by their skin. Nevertheless, adults can also be infected by causative agents of ringworm. Tinea is mainly caused by specific fungal genera including Microsporum, Epidermophyton and Trichophyton, which are all moulds. Generally, ringworm, which is a type of cutaneous mycoses, is of various types. Tinea corporis is ringworm of the skin; Tinea capitis is ringworm of the scalp; Tinea cruris (also known as jock itch)is the ringworm of the groin; and Tinea pedis (also known as athlete’s foot) is ringworm of the feet (Table 2). Dermatophytes have high affinity for keratinized tissues of the body especially the epidermis of the skin where dead keratinized tissues are located.

Table 2. Synopsis of cutaneous mycoses

Dermatophytes like the fungi that cause superficial mycoses are also among the least invasive fungal organisms because they do not penetrate deep tissues (e.g.,) of the body but only colonize the keratinized outer layer of the skin especially the dead layers of the outer skin and other keratinized parts of the body. Dermatophytes that reside naturally in the soil are known as geophilic fungi (for example, Microsporum gypseum) while those whose natural habitat is animals such as cattle, horses, dogs and cats are known as zoophilic fungi (for example, Microsporum species including M. canis, M. gallinae, M. nanum and Trichophyton species including T. verrucosum and T. equinum). Anthropophilic fungi are dermatophytes that naturally reside on the body of humans (for example, Epidermophyton species and Trichophyton species); and they cause infection following the destabilization of the body’s normal flora.

Cutaneous mycoses are less-debilitating fungal infections even though they are prevalent in most parts of the world. They are contagious and can spread from person to person via direct body contact with infected persons. Animal-human contacts and the use of personal items of infected individuals such as bathing soaps, bathtub and towels are other predisposing factors to the acquisition of a dermatophyte infection. Dermatophytoses usually arise following inflammatory activities caused by the invading fungus on the site of infection, and this is normally seen as itching, irritating and erythematous scaling and skin discolouration at affected body sites.

Generally, cutaneous mycoses are localized fungal diseases that do not disseminate or spread to other parts of the body, and their name corresponds to the particular site of the body that is affected (Table 2). Dermatophytoses can best be treated with topical and oral antifungal agents. Proper medical attention is usually required to bring the infection under control, since infection with dermatophytes may persist for some while in the affected individual. Trichophyton, Epidermophyton and Microsporum are the three main genera of fungi that are responsible for causing cutaneous mycoses and/or dermatophytosis in human population. Trichophyton species are spore formers and some notable species that produce both macroconidia and microconidia include T. rubrum with lateral microconidia and cylindrical macroconidia (Figure 4).

Figure 4. Microconidia and macroconidia of Trichophyton rubrum. Photo courtesy: https://www.microbiologyclass.com

Other notable Trichophyton species that produce both macroconidia and microconidia include: T. metangrophytes with macroconidia and clustered grape-like microconidia (Figure 5), T. tonsurans with arthrospores, macroconidia and elongated microconidia (Figure 6), T. soudanensewith reflective and branching arthrospores (Figure 7). On the other hand, Epidermophyton floccosum is unique because it is the only fungal pathogen present in the genus Epidermophyton. Epidermophyton floccosum produces a characteristic macroconidia which is club-shaped (Figure 8). It also produces chlamydospores that are attached to the fungal thallus (Figure 8). Microsporum species (dermatophytes of the skin and hair) including M. audouinii (Figure 9) and M. gypseum (Figure 10) produce characteristic multicellular macroconidia which aids in their identification from either environmental or clinical samples.

Figure 5. Microconidia and macroconidia of Trichophyton mentagrophytes. Photo courtesy: https://www.microbiologyclass.com
Figure 6. Macroconidia and microconidia of Trichophyton tonsurans. Photo courtesy: https://www.microbiologyclass.com
Figure 7. Reflective and branching arthrospores of Trichophyton soudanense. Photo courtesy: https://www.microbiologyclass.com
Figure 8. Macroconidia and chlamydospores of Epidermophyton floccosum. Photo courtesy: https://www.microbiologyclass.com
Figure 9. Macroconidia and terminal chlamydospores ofMicrosporum audouinii. Photo courtesy: https://www.microbiologyclass.com
Figure 10. Macroconidia of Microsporum gypseum. Photo courtesy: https://www.microbiologyclass.com

SUBCUTANEOUS MYCOSES

Subcutaneous mycoses are fungal infections that affect the subcutaneous tissues below the skin, and the bone and other tissues occasionally. The subcutaneous tissue or layer is the part of the skin that lies beneath the skin and it contains large deposits of fats (for example, in the buttocks and thigh regions). Apart from affecting the subcutaneous tissues of the skin, subcutaneous mycoses also involve the dermis layer of the skin. Dermis is the thick inner layer of the skin that lies beneath the epidermis, and it is the main layer of living skin cells. Subcutaneous mycoses rarely involve deeper tissues of the body even though they extend beneath the tissues that underlie the skin. This type of mycoses occurs when certain pathogenic fungi that reside in the soil and on plantation are introduced into the body through trauma or skin injury. Subcutaneous mycoses include chromoblastomycosis (chromomycosis), sporotrichosis, mycetoma/madura foot (maduromycosis) and phaeohyphomycosis (Table 3). Chromoblastomycosisis caused by five recognized dematiaceous moulds which are Fonsecaea pedrosoi, F. compacta, Cladophialophora carrionii, Rhinocladiella aquaspersa and Phialophora verrucosa which form phialides. These fungi are the main causative agents of chromoblastomycosis in humans. Chromoblastomycosis is a widespread and globally distributed chronic fungal infection of the subcutaneous tissue and skin. It is usually caused by the traumatic inoculation of some specific type of dematiaceous fungi as aforementioned, into the skin. Microscopic illustrations of the mature and young phialides of P. verrucosa are shown in Figure 11 and Figure 12. The fungal agents that cause subcutaneous mycoses are numerous excluding sporotrichosis which is only caused by a particular fungus known as Sporothrix schenckii.

Table 6.3: Synopsis of subcutaneous mycoses

Figure 11. Young phialides of Phialophora verrucosa. Photo courtesy: https://www.microbiologyclass.com

S. schenckii is a dimorphic fungus that is found in the soil and on agricultural plantations.It is the causative agent of sporotrichosis. Sporotrichosis occur worldwide especially in tropical and subtropical countries. The disease is initiated following an outdoor activity in which the fungus (S. schenckii)is traumatically inoculated into the host’s body through contaminated soil or materials. Granulomatous lesions are usually developed in the subcutaneous tissues that underlie the skin of S. schenckii infected individuals. These lesions may develop into an ulcerative lesion that is capable of dissemination through lymphatic vessels or bloodstream to other parts of the body. Deep mycoses involving S. schenckii is rare; and lymphatic drainage of the infection when it occurs usually results in the development of multiple lesions in the affected individual.

Sporotrichosis is an occupational disease that is very common amongst gardeners, farmers and horticulturists. The disease is usually a self-limiting subcutaneous mycoses but treatment for the mycoses is usually done using oral antifungal agents (for example, itraconazole or ketoconazole), oral administration of saturated potassium iodide solution and by surgical removal of lesions or nodules due to the disease. Most subcutaneous mycoses are occupational fungal diseases that mainly affect people who do or work in certain types of occupation such as miners, farmers, construction workers, gardeners, horticulturists, forest keepers and florists. This is because the group of fungi that causes subcutaneous mycoses (as shown in Table 3) is ubiquitously found in the soil and on plants as saprophytic organisms. They only infiltrate the human body by chance through wound infections on the skin or through abrasions and traumatic inoculation of the causative agent into the skin.

Pathogenic fungi that cause subcutaneous mycoses enter the body through traumatic inoculation or wound injury involving sharp contaminated objects or materials containing the infecting fungal organisms. After inoculation, the fungi or fungus migrate to the subcutaneous connective tissues and lymphatic vessels of the body (especially those that underlies the skin) where they elicit local, self-limiting and chronic fungal infections that usually results in the formation of granulomatous lesions. Life-threatening infections associated with subcutaneous mycoses are rare in humans. But when deep or systemic mycoses due to subcutaneous fungal infection occur, the infections become broad and then affect other vital tissues and organs of the body such as the bones.        

SYSTEMIC MYCOSES

Systemic mycoses are fungal infections that affect deep tissues and organs of the body. They generally start off as pulmonary infections in affected individuals, and then later assume a general circulation in the body. Systemic mycoses can also be called endemic mycoses because of their geographic distribution; and they can also be called deep mycoses because of their disseminated form in the body. They are the most disseminating, deadly and severe forms of mycoses out of all the known forms of fungal mycoses in humans. Systemic mycoses generally involve the internal body organs of humans such as the lungs, heart, liver, bones and kidney; and they also show cutaneous and subcutaneous involvement when the infection is disseminated through the bloodstream. Systemic mycoses are mainly caused by dimorphic or diphasic fungi excluding Cryptococcosis neoformans (the causative agent of cryptococcosis) which only exist in the yeast form (Table 4).

Table 4. Synopsis of systemic (endemic) mycoses

C. neoformans though a causative agent of systemic mycoses also causes opportunistic mycoses in immunocompromised people. Thus, agents of systemic (endemic) mycoses exist in two main forms: the yeast phase and the mould or mycelia phase. Systemic mycoses are usually limited to certain geographical location, and thus they are often referred to as endemic mycoses because they are usually prevalent in certain ecological niches of the world as shown in Table 4. The viable spores or conidia of causative agents of systemic mycoses grow at ambient temperatures (for example, 25oC) as moulds in the environment and as yeasts at body temperature (for example, 37oC) within the human host. Spores of dimorphic fungi are easily aerosolized and this increases their infectious rate in nature. Systemic mycoses include histoplasmosis (caused by Histoplasma capsulatum), blastomycosis (caused by Blastomyces dermatitidis), coccidioidomycosis (caused by Coccidioides immitis) and paracoccidioidomycosis (caused by Paracoccidioides brasiliensis). Histoplasma, Blastomyces, Coccidioides and Paracoccidioides are found in the fungal division Ascomycota.Brief details of systemic or endemic mycoses are shown in Table 4.

Systemic mycosis is initiated following the introduction of fungal spores of some specific dimorphic fungi into the body through inhalation of dust or aerosols containing infectious fungal spores. The spores get into the lungs where they grow to cause primary mycosis (for example, pulmonary disease of the lungs) which is usually self-limiting and asymptomatic in some cases. However, extra-pulmonary mycosis can ensue when the disease becomes chronic and disseminated, affecting other vital organs of the body such as the skin, heart, liver and the kidney. Secondary systemic mycoses usually occur in people with compromised immunity such as people on chemotherapy, HIV/AIDS patients and people on immunosuppressive drugs. Systemic mycoses unlike some other fungal infections (for example, superficial mycoses) are rarely communicable in nature; and they may present with severe pathological signs and symptoms that are different and more severe than those of superficial, subcutaneous or cutaneous mycoses.

Agents of systemic (endemic) mycoses are ubiquitously found in the soil from where their viable spores or conidia become aerosolized to cause human infection after inhalation of infectious spores. However, an intact and strong immunity is vital to preventing systemic mycosis in humans. Systemic mycoses are mostly common amongst immunocompromised individuals and in people with other predisposing health conditions such as those on chemotherapy or transplant patients as aforementioned. They rarely occur in people with strong and intact immunity.

OPPORTUNISTIC MYCOSES

Opportunistic mycoses are fungal infections caused by opportunistic fungi that only affect people with weakened immune system. Severely sick individuals and debilitated patients with weakened immune system are more prone to infections with opportunistic fungal organisms. Opportunistic mycoses do not occur in healthy people whose immunity is still strong and intact. Opportunistic mycoses are fungal infections of the body which occur almost exclusively in debilitated patients whose normal defense mechanisms against infections are impaired; and they are usually caused by fungal organisms with moderate or low virulence nature. Such patients include those on chemotherapy, cancer patients, patients who use corticosteroids, organ transplant patients and patients with HIV/AIDS infection. The fungi that cause opportunistic mycoses are usually fungal organisms that have a very low inherent virulence as aforementioned; and thus lack the natural ability to cause infection in individuals whose immune system is still intact or strong. Only people with poor or compromised immunity are mostly affected by opportunistic fungi. Opportunistic mycoses include candidiasis, aspergillosis, mucormycosis, systemic penicilliosis and pneumocystis pneumonia and cryptococcosis (Table 5). It is noteworthy that all opportunistic mycoses are exogenous infections acquired from the environment through the inhalation of viable fungal spores of their respective causative fungal agents (Table 5). The only exclusion to this is candidiasis – which is endogenous, because the causative agent (C. albicans) is normally a part of the host’s normal microflora.

Table 5. Synopsis of opportunistic mycoses

TREATMENT AND PREVENTION OF FUNGAL INFECTIONS

Fungal infection is treated using antifungal agents. Some of the antifungal agents used for the treatment of mycoses in humans include polyenes (for example, amphotericin B and nystatin) which are cidal in action and binds to the fungal ergosterol membranes to disrupt the integrity of the fungal cell membrane; azoles (for example, itraconazole, ketoconazole, voriconazole, fluconazole, miconazole) which are static in action and inhibit the synthesis of ergosterol; griseofulvin, which is static in action and inhibits fungal growth by binding to microtubules during mitosis; 5-fluorocytosine or flucytosine, which is an antimetabolite and inhibits nucleic acid synthesis and protein synthesis; echinocandins (for example, caspofungin, micafungin) which are static in action and inhibits the synthesis of chitin and glucan in fungal cell wall; and allylamines (for example, terbinafine) which are static in action and inhibit the synthesis of ergosterol like the azoles.  

PREVENTION AND CONTROL OF FUNGAL INFECTIONS The prevention and control of mycoses is largely dependent on avoiding exposure to fungal spores or conidia and limiting contact with natural reservoirs of most fungal organisms. An intact immunity is vital to the prevention of fungal infections in humans. Thus, people should avoid some risk factors such as prolonged antibiotic usage and other factors that weaken the body’s natural defense against fungal infection. People who work in certain type of occupation such as farmers, horticulturists, construction workers and forest workers should wear protective footwear and face mask to avoid traumatic introduction of pathogenic fungi into the body as well as the introduction of fungal spores into the body via the nostrils.

While some fungal infections are non-communicable, others such as superficial mycoses (for example, ringworm) are infectious; and avoidance of body contact or sharing of towels, soap and bathtub with infected people is critical to the prevention of most superficial mycoses in human population. Fungicides and other antimicrobial agents should be used on the natural reservoirs of fungi (for example, soil) to avoid the aerosolization of their spores which when inhaled can lead to mycoses in humans. People working in dusty areas should always wear protective face mask to avoid the inhalation of fungal spores.

Further reading

Anaissie E.J, McGinnis M.R, Pfaller M.A (2009). Clinical Mycology. 2nd ed. Philadelphia, PA: Churchill Livingstone Elsevier. London.

Baumgardner D.J (2012). Soil-related bacterial and fungal infections. J Am Board Fam Med, 25:734-744.

Calderone R.A and Cihlar R.L (eds). Fungal Pathogenesis: Principles and Clinical Applications. New York: Marcel Dekker; 2002.

Champoux J.J, Neidhardt F.C, Drew W.L and Plorde J.J (2004). Sherris Medical Microbiology: An Introduction to Infectious Diseases. 4th edition. McGraw Hill Companies Inc, USA.       

Gladwin M and Trattler B (2006). Clinical Microbiology Made Ridiculously Simple. 3rd edition. MedMaster, Inc., Miami, USA.

Larone D.H (2011). Medically Important Fungi: A Guide to Identification. Fifth edition. American Society of Microbiology Press, USA.

Madigan M.T., Martinko J.M., Dunlap P.V and Clark D.P (2009). Brock Biology of Microorganisms, 12th edition. Pearson Benjamin Cummings Inc, USA.

Stephenson S.L (2010). The Kingdom Fungi: The Biology of Mushrooms, Molds and Lichens. First edition. Timber Press.

Sullivan D.J and Moran G.P (2014). Human Pathogenic Fungi: Molecular Biology and Pathogenic Mechanisms. Second edition. American Society of Microbiology Press, USA.

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