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C H A P T E R 61

Medical Parasitology

Thomas R. Fritsche, M.D., Ph.D., Rangaraj Selvarangan, B.V.Sc., Ph.D.

Laboratory Methods 1120Examination of Blood 1121Examination of Fecal Specimens 1122Examination of Urogenital and Other Specimens 1124

(Sputa, Aspirates, Biopsies)Parasite Culture Techniques 1125Immunodiagnostic Methods 1125Molecular Diagnostic Methods 1127Quality Assurance, Quality Improvement, and 1127

Safety

Blood and Tissue Protozoa 1127Malaria 1127Babesiosis 1134Hemoflagellates 1134Toxoplasma gondii 1136Opportunistic Free-Living Amebae 1137

Intestinal and Urogenital Protozoa 1138Amebae and Blastocystis hominis 1138Flagellates 1142Ciliates 1144Coccidia 1144Microsporidia 1146

Intestinal Helminths 1146Nematodes 1147Cestodes 1150Trematodes 1152

Tissue Helminths 1155Nematodes 1155Cestodes 1157Trematodes 1159

Medically Important Arthropods 1159Biological Characteristics 1159Mechanisms of Injury 1159Laboratory Approaches to Arthropod 1160

IdentificationInsects 1160Arachnids 1162Classes of Lesser Medical Importance 1163Millipedes 1163

Parasitic Infections and the 1165Immunocompromised Host

References 1165

KEY POINTS• Accurate diagnosis of parasitic infections usuallydepends on macroscopic or microscopic examination of

specimens that have been appropriately collected and preserved.Thick and thin blood smears are useful to detect and characterizeorganisms found in the blood. Fecal specimens may either be freshor placed into fixatives such as formalin and polyvinyl alcohol.• Immunodiagnostic methods for parasitology include detection ofboth antibodies and antigens. Established enzyme immunoassaysinclude antigen tests for Plasmodium spp. in blood or serum; Giardialamblia, Cryptosporidium spp., and Entamoeba histolytica in feces;Trichomonas vaginalis in vaginal swabs. Direct fluorescent assays arealso useful for identifying organisms in primary specimens.• Molecular diagnostic methods are now emerging based onamplification techniques that offer high levels of sensitivity andspecificity for both diagnosis and monitoring of parasitic diseases.• The diagnosis of malaria should be considered in the differentialdiagnosis of unexplained fever with the history of travel in endemicgeographic regions. Thick and thin blood smears are complementaryfor detecting and identifying the infecting Plasmodium spp. based onthe varieties of developmental stages, presence of malarial pigment,and stippling seen in infected erythrocytes.• Other protozoal infections include babesiosis and trypanosomiasisfound in blood, leishmaniasis (causing cutaneous, mucocutaneous,and visceral forms of disease), and toxoplasmosis, often affecting thecentral nervous system following congenital infection and in patientswith the acquired immunodeficiency syndrome (AIDS).• Amebae are ingested as cysts, resulting in infection of the colonand passage of both cysts and trophozoites in the feces. The resulting

diseases are amebic dysentery, amebic colitis, and liver abscesses.Diagnosis is made by microscopic examination of stool and byserological testing for antibodies in serum.• Flagellates include Giardia lamblia, which causes diarrhea fromingestion of contaminated water and is diagnosed by findingtrophozoites or cysts in feces. Trichomonas vaginalis can be detectedin vaginal wet mounts by its characteristic motion.• Coccidia (Isospora, Cryptosporidium, and Cyclospora) andmicrosporidia can cause protracted diarrhea in immunosuppressedindividuals such as those with AIDS.• Intestinal helminths include the nematodes (roundworms),cestodes (tapeworms), and trematodes (flukes). These organismsreside as adults in the gastrointestinal tract or in other locations (liver,lung, blood). Knowledge of their life cycles and zoogeography withintermediate hosts are critical for establishing the parasitic stage inpresumed infection. Eggs, larvae, or adult forms (from 1 mm to>10 m in length, depending upon species) can be recovered fromstool, urine, or sputum.• Tissue helminths include filaria (larvae found in blood and also onskin biopsy), Trichinella (in muscle), Strongyloides (disseminatedinfection), and hydatidosis (large cystic lesions in the liver or lungs),among others.• Arthropods cause disease through direct tissue invasion,envenomation, vesication, blood loss, transmission of infectious agents,hypersensitivity reactions, and psychological manifestations.Characteristics necessary for identification can be maintained bypreserving the organisms in alcohol (ticks, mites, fleas, lice), by dryingthem (winged forms) after killing them with fumes of organic solvents,or killing with hot water (maggots) and subsequent storage in alcohol.

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generally not appropriate or available for smaller laboratories. The recentdevelopment of immunocapture assays for the detection of Plasmodium-specific lactate dehydrogenase or HRP-II appears to provide a high degreeof sensitivity and specificity in the diagnosis of malaria. Several versions ofthese tests, configured as ‘dipstick’ methods, are especially promising insituations where ease of performance is critical and usual laboratoryfacilities are lacking (Palmer, 1998; Piper, 1999; Marx, 2005).

Life CycleMalarial parasites undergo a sexual phase (sporogony) in Anophelesmosquitoes that results in the production of infectious sporozoites and anasexual stage (schizogony) in humans that results in the production ofschizonts and merozoites (Fig. 61–1). In the blood stream, somemerozoites eventually differentiate into gametocytes (gametogony),which, when ingested by female anopheline mosquitoes, mature into the male microgametes and the female macrogametes. Fusion of amicrogamete and a macrogamete results in the formation of the motileookinete, which migrates to the outside of the stomach wall and forms an

oocyst. Within the oocyst, numerous spindle-shaped sporozoites areformed. The mature oocyst ruptures into the body cavity, releasing thesporozoites, which then migrate through the tissues to the salivary glands,from which they are injected into the vertebrate host as the mosquitofeeds. The time required for development in the mosquito ranges from8–21 days.

The sporozoites injected into the vertebrate host reach the hepaticparenchymal cells within minutes and initiate the proliferative phaseknown as exoerythrocytic schizogony. Release of merozoites fromruptured hepatic schizonts initiates the blood stream infection orerythrocytic schizogony and, eventually, the clinical symptoms of malaria.P. vivax and P. ovale differ from P. falciparum and P. malariae in that truedisease relapses of the former species may occur weeks to months followingsubsidence of previous attacks. This occurs as a result of renewedexoerythrocytic and, eventually, erythrocytic schizogony from latent hepaticsporozoites, which are known as hypnozoites (Krotoski, 1982). Recurrencesof disease due to P. falciparum or P. malariae, called recrudescences, arisefrom an increase in numbers of persisting blood stage forms to clinically

MAN

MOSQUITO

Oocyst containingsporocytes

Oocyst rupturessporozoites liberated

Sporozoites in salivary glands(infective stage)

Sporozoites injected by mosquito

Oocyst onstomach wall

Ookinete

Macrogamete

Microgamete

Exflagellatingmicrogametocyte

Microgametocyte

Microgametocyte

Macrogametocyte

Macrogametocyte

Fertilization

Penetrate parenchymalcells of liver

Immatureschizont

Immatureschizont

Matureschizont Penetrate

red blood cells

Ring-formtrophozoite

Merozoites

Merozoites

Maturetrophozoite

Growingtrophozoite

Mature schizont

Immatureschizont

EXOERYTHROCYTICSCHIZOGONY

ERYTHROCYTICSCHIZOGONY

Figure 61–1 Life cycle of malarial parasites. (Courtesy of the Centers for Disease Control, Parasitology Training Branch, Atlanta, GA.)

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months or more with the other Plasmodium species. The commonpresenting symptoms of malaria include chills and fever, which are oftenassociated with splenomegaly. In the early stages of the disease, the febrileepisodes occur irregularly but eventually become more synchronous,assuming the usual tertian (P. vivax, P. falciparum, and P. ovale) or quartan(P. malariae) periodicity. Patients with malaria may develop anemia andmay have other manifestations, including diarrhea, abdominal pain,headache, and muscle aches and pains. P. falciparum malaria can result in high (50%) parasitemias, which can lead to severe hemolysis withhemoglobinuria and profound anemia. Erythrocytes infected withgrowing trophozoites and schizonts of P. falciparum become sequestered insmall vessels of the body and may lead to occlusion of these vessels,causing symptoms related to capillary obstruction and tissue anoxia.Involvement of the brain is known as cerebral malaria, in which thepatient becomes disoriented, progressing to delirium, coma, and often

death. Exchange transfusion may be lifesaving in severe P. falciparuminfections (Nielson, 1979; Powell, 2002).

The course of untreated malaria depends on the species. Most fatal casesof malaria are due to P. falciparum. In nonfatal cases, the febrile paroxysmsbecome less severe with time and the disease gradually subsides. Patientswith P. vivax or P. ovale infection may have relapses after many months or,occasionally, years. Persons with P. falciparum and P. malariae infectionmay have symptom-free periods but suffer from sporadic recrudescencesowing to persisting low-grade parasitemia. Relapses and recrudescencesmay be associated with changes in the host’s defense mechanisms orpossibly with antigenic changes in the infecting organisms.

Peripheral smears may show leukocytes that contain malaria pigment.Increased reticulocyte counts occur commonly and are associated with therapid erythrocyte turnover. The presence of greatly enlarged platelets alsomay be noted on peripheral blood films and occur as a result of their rapid

Figure 61–5 Plasmodium ovale. 1, Young ring-shapedtrophozoite. 2–5, Older ring-shaped trophozoites. 6–8, Older ameboid trophozoites. 9, 11, and 12, Doubly infected cells, trophozoites. 10, Doublyinfected cell, young gametocytes. 13, First stage of theschizont. 14–19, Schizonts, progressive stages. 20, Mature gametocyte. Free translation of legendaccompanying original plate in Guide pratiqued’examen microscopique du sang appliqué audiagnostic du paludisme’ by Georges Villain.Reproduced with permission from Biologie Medicalesupplement, 1935. (Courtesy of Aimee Wilcox,National Institutes of Health Bulletin No. 180, USPHS.)

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recognized around growing trophozoites as a pink halo rather than thedistinct granules seen in thin films. The ameboid character of P. vivaxtrophozoites is not as evident in thick films, but the number of merozoites inmature schizonts is helpful. Macro- and microgametocytes cannot usually bedifferentiated. The distinctive sausage shape of P. falciparum gametocytes isstill evident, although they may be more stubby than in thin films.Gametocytes of the other species can be detected and are easily differentiatedfrom host cell nuclei by the presence of refractile hemozoin pigment.

Mixed infections occur occasionally (about 5% of the time) but cautionshould be used in making such diagnoses unless there is definite evidence oftwo separate populations of parasites. The most common mixed infectionsare P. falciparum and P. vivax. Finding gametocytes of P. falciparum in a personobviously infected with P. vivax is diagnostic.

There are multiple artifacts that may be confused with malarial parasitesin thick and thin films. The most common artifact in thin films are bloodplatelets superimposed on red blood cells. These platelets should bereadily identified because they do not have a true ring form, do not showdifferentiation of the chromatin and cytoplasm, and do not containpigment. Clumps of bacteria or platelets may be confused with schizonts.At times, masses of fused platelets may resemble gametocytes of P.falciparum but do not show the differential staining or the pigment.Precipitated stain and contaminating bacteria, fungi, or spores may also beconfused with these parasites.

Species-specific serologic tests for malaria are particularly useful forepidemiologic surveys and for detection of infected blood donors. Suchtests do not reliably differentiate current from past infection, however.Sensitive and specific IFA tests using antigens from the four human speciesare available from the CDC (Wilson, 1995). Assays for the direct detectionof malarial antigens in blood are especially promising (see LaboratoryMethods).

BabesiosisLike malarial parasites, the etiologic agents of babesiosis or piroplasmosisare apicomplexan protozoa found worldwide that infect erythrocytes,often producing a febrile illness of variable severity. Unlike malaria,babesiosis is transmitted by ticks and is found in a variety of animalspecies that serve as reservoirs (Krause, 2002).

Human infections in the United States occur predominantly in thenortheastern and midwestern states, where the rodent parasite Babesia microtiis responsible for infection (Homer, 2000). Ixodes scapularis is the usual tickvector. Recent studies have implicated another, as yet unnamed, Babesiaspecies (tentatively known as WA1) as being responsible for disease in thewestern United States. This parasite, associated with disease in Washingtonstate and California, is thought to be transmitted by the western black-leggedtick, Ixodes pacificus (Quick, 1993; Persing, 1995). In Europe, the canine

parasite Babesia divergens, transmitted by Ixodes ricinus, infects humans and arecent report of a B. divergens-like infection in Washington State expands therange of known human cases (Herwaldt, 2004).

The spectrum of babesiosis varies from latent, subclinical infection tofulminant, hemolytic disease. Fatalities have been reported, especially insplenectomized or immunocompromised individuals. Immunocompetentpersons may experience symptoms similar to those of malaria, includingfever, chills, malaise, and anemia, although without recognizableperiodicity. Investigation of an outbreak caused by B. microti on NantucketIsland in New England showed that some symptomatic patients harboredthe parasite for months and others showed serologic evidence of infectionwithout a history of clinical disease (Ruebush, 1980). Other evidence isaccumulating indicating that chronic subclinical infections may not beuncommon (Persing, 1995).

Babesia parasites multiply in erythrocytes by schizogony but do notproduce gametocytes. Although trophozoites of many species appear pear-shaped at some point in their development, those of B. microti usuallyappear as delicate ring forms that may be easily confused with those ofmalarial parasites, especially P. falciparum (Fig. 61–6A) (Healy, 1980; Homer,2000). Babesia trophozoites can be differentiated from those of malarialparasites by the presence of multiple rings in one cell that may form a tetrad(Maltese cross) and the absence of large, growing trophozoites andgametocytes. Also, Babesia-infected cells lack hemozoin pigment, which ispresent in Plasmodium-infected cells. History of residence in or travel toendemic areas, or of a recent tick bite, might suggest Babesia infection.Serologic tests (IFA) for both B. microti and WA1 are available from theCDC on referral from state health departments. Serology tests for malariaare negative in babesiosis, although patients with malaria may cross-reactin the Babesia serologies (Wilson, 1995).

HemoflagellatesThe hemoflagellates of humans and animals are members of the orderKinetoplastida and are characterized by the presence of a large mito-chondrion known as a kinetoplast, which contains enough DNA to beseen by light microscopy when treated with Giemsa stain. Two generaimportant in human disease are Trypanosoma and Leishmania. Members ofboth genera are transmitted by arthropod vectors and have animal hoststhat serve as reservoirs.

The kinetoplastida assume different morphologic forms depending ontheir presence in vertebrate hosts, including humans, or their insect vectors(Fig. 61–7). The amastigote stage is spherical, 2–5 μm in diameter, anddisplays a nucleus and kinetoplast. By definition an external flagellum islacking, although an axoneme (the intracellular portion of the flagellum)is apparent at the ultrastructural level. Amastigotes may be found inhuman or animal hosts infected with either T. cruzi or Leishmania spp.,

A B C

D E F

Figure 61–6 A, Human infection with Babesia microti; note high parasitemia and multiple-infected red cell (oil immersion). B, Trypanosoma sp. in stained blood film; notenucleus, kinetoplast, and undulating membrane (oil immersion). C, Leishmania mexicana amastigotes in impression smear of thigh lesion; Giemsa stain (oil immersion). D, Pseudocyst of Toxoplasma gondii in brain tissue (hematoxylin and eosin [H&E]; oil immersion). E, Cutaneous rosette of T. gondii tachyzoites in an immunocompromisedpatient (H&E; oil immersion). F, Tachyzoites of T. gondii recovered from a bronchoalveolar lavage specimen from an individual infected with the human immunodeficiencyvirus (Giemsa stain; oil immersion).

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The nuclei of I. bütschlii trophozoites and cysts have a large, centrallylocated karyosome frequently surrounded by achromatic granules thatmay not be distinct but appear only as a muddy karyolymph space or halo.In some nuclei, the halo is clear without evident achromatic granules,making the organism indistinguishable from E. nana. Cysts of I. bütschliicontain a single nucleus, in which the karyosome is often eccentric with anearby crescent of achromatic granules (see Figs. 61–9, 61–10, and 61–12).The cyst is characterized by a prominent vacuole of glycogen that stainsreddish brown in iodine-stained wet mounts, thus the name of the

organism. Glycogen is dissolved by aqueous fixatives and may not bedemonstrable in material that has been stored.

Blastocystis hominisB. hominis is an ameba-like protozoan that inhabits the large bowel and isfrequently found in stool specimens of asymptomatic individuals. Somestudies have linked heavy infections to symptomatic intestinal disease,although this remains controversial (Markell, 1986; Sheehan, 1986;Miller, 1988; Zierdt, 1991; Stenzel, 1996). Blastocystis may assume one of

Table 61–9 Morphology of Trophozoites of Intestinal Amebae

Species Size (in Motility Nucleus Peripheral Karyosomal Cytoplasm Inclusions Diameter Numbers‡ Chromatin Chromatin Appearance or Length)

Entamoeba 10–60 μm; usual Progressive, 1 Fine granules; Small, discrete; usually Finely granular Erythrocytes histolytica/E. range, 15–20 μm with hyaline, Not visible in usually evenly central but occasionally occasionally in invasive dispar commensal form*; finger-like unstained distributed and eccentric forms. Noninvasive

over 20 μm for pseudopods preparations uniform in size contain bacteria invasive form†

Entamoeba 5–12 μm; usual Usually 1hartmanni range 8–10 μm nonprogressive Not visible in Similar to E. Small, discrete, often Finely granular Bacteria

but may be unstained histolytica eccentric progressive preparations occasionally

Entamoeba 15–50 μm; usual Sluggish, 1coli range 20–25 μm nonprogressive Often visible in Coarse granules, Large, discrete, usually Coarse, often Bacteria, yeasts, other

with blunt unstained irregular in size eccentric vacuolated materials pseudopods preparation and distribution

Endolimax nana 6–12 μm; usual Sluggish, usually 1 None Large, irregularly shaped Granular, Bacteria range 8–10 μm nonprogressive Visible occasionally vacuolated

with blunt in unstained pseudopods preparations

Iodamoeba 8–20 μm; usual Sluggish, usually 1 None Large, usually central. Coarsely Bacteria, yeasts, or other bütschlii range 12–15 μm nonprogressive Not usually Surrounded by refractile, granular, material

visible in unstained achromatic granules. vacuolated preparations These granules are often

not distinct even in stained slides

Dientamoeba 5–15 μm; usual Pseudopods are 2 None Large cluster of 4–8 Finely granular, Bacteria fragilis§ range 9–12 μm angular, serrated, (In approximately granules vacuolated

or broad lobed 20% of organismsand hyaline, only 1 nucleus is almost present.) Nuclei transparent invisible in

unstained preparations

* Usually found in asymptomatic or chronic cases; may contain bacteria. † Usually found in acute cases; often contain red blood cells. ‡ Visibility is for unfixed material. Nucleimay sometimes be visible in fixed material. § A flagellate (see text).

Source: adapted from Brooke MM, Melvin DM: Morphology of Diagnostic Stages of Intestinal Parasites of Man. USDHEW PHS Publication No. 1966, 1969.

Figure 61–12 Nuclei of amebae. This drawing shows some of the various appearances of amebic nuclei in stained preparations. (Dientamoeba fragilis is a flagellate; see text.)

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Although systemic reactions may occur in individuals who have beenpreviously sensitized, fatalities are rare (Goddard, 2002).

CrustaceansCrustaceans of medical importance are primarily those species that serve ashosts for larval stages of several different helminths. Several genera of crabsand crayfish are intermediate hosts for the metacercariae of various species oflung fluke (Paragonimus spp.) found around the world. Copepods arecommon microscopic zooplankton, certain species of which serve as firstintermediate hosts for the nematodes D. medinensis and Gnathostomaspinigerum and for cestodes of the genera Diphyllobothrium and Spirometra.

PentastomidsPentastomes, or tongue worms, are arthropods of uncertain affinitiesowing to a lack of morphologic characteristics. Adult stages are worm-like organisms that live in the nasal passages of certain predatoryreptiles, birds, and mammals. Larval stages resemble mites and reside inrodents, herbivores, and freshwater fish. Human liver and lunginfections with larval stages have been reported from Asia and Africa.Adult stages have been recovered from the nasopharynx of individualsfrom the Middle East and Africa, where they are responsible for anobstructive condition known as halzoun (Beaver, 1984; Strickland,2000).

Table 61–13 Parasitic Infections in Compromised Hosts

Infection Predisposing Host Abnormalities Comments References

Intestinal Protozoa Cryptosporidiosis AIDS (especially CD4+ <200/μL), Severe protracted diarrhea (up to 17 L/day.) May have extraintestinal Wittner, 1993;

transplantation, antineoplastic involvement including pancreas, biliary tract, and lungs. Limited Thielman, 1998 chemotherapy therapy available, is not curative

Isosporiasis AIDS, transplantation, antineoplastic Severe protracted diarrhea. Extraintestinal involvement of regional lymph Wittner, 1993; chemotherapy nodes may be seen. Effective therapy is available Thielman, 1998

Cyclosporiasis AIDS, probably other immunosuppression Severe protracted diarrhea clinically similar to cryptosporidiosis and Wittner, 1993; isosporiasis. Responds to trimethoprim–sulfamethoxazole Thielman, 1998

Microsporidiosis AIDS, other severe immunosuppression Various syndromes: Wittner, 1993; 1. Multisystem disease Thielman, 1998 2. Enteritis with severe diarrhea (most frequent)3. Ocular infection4. Hepatobiliary with granulomas, hepatic necrosis or cholangitis5. Skeletal muscle diseaseExamination of urinary sediment with appropriate stain may allow diagnosis on nonenteric syndromes and some cases of enteric disease

Giardiasis Common variable immunodeficiency, Prolonged diarrhea with malabsorption. AIDS is not a predisposing condition Thielman, 1998 X-linked agammaglobulinemia

Blood and Tissue Protozoa Granulomatous amebic AIDS and other immunocompromised states Usually caused by amebae of the genera Acanthamoeba or Balamuthia. Martinez, 1997 encephalitis Produces subacute or chronic central nervous system infection but may be

acute in severely immunosuppressed hosts with dissemination Toxoplasmosis AIDS with CD4+ usually <100/μL and Usually result of reactivation of cysts from previous infections. Often McCabe, 1993

other immunocompromised states. disseminated disease with multiorgan involvement or multifocal CNS Heart transplant, donor seropositive and lesions. Can cause pneumonitis resembling that caused by Pneumocystis recipient seronegative jiroveci. May cause chorioretinitis. Can occur after transplantation of bone

marrow but usually mild. Heart transplant with donor serologically positive and recipient serologically negative may lead to severe, often fatal toxoplasmosis

Leishmaniasis AIDS, other immunosuppression Limited influence on cutaneous leishmaniasis. Susceptibility to visceral Herwaldt, 1999 leishmaniasis increased but not disease severity. More likely to relapse after treatment

American AIDS, lymphoblastic lymphoma, cardiac In AIDS – central nervous system often involved, myocarditis, skin lesions Mileno, 1998; trypanosomiasis transplantation, other immunosuppression Markell, 1999 (Chagas disease) Babesiosis Splenectomy Usually subclinical infection in those with intact host defenses. Mileno, 1998;

Splenectomized patients usually develop clinically evident disease which Markell, 1999 can be fatal

Helminth Strongyloidiasis Immunosuppression for transplantation Because of endogenous autoinfection; hyperinfection or disseminated Mileno, 1998;

or by cancer chemotherapy or adrenal infection can develop and present as pneumonia or severe intestinal Markell, 1999 corticosteroids or lymphoma. AIDS is not disease. Gram-negative sepsis or Gram-negative meningitis can result a major predisposing factor from translocation of intestinal bacteria via invading larvae. Should check

for strongyloidiasis before immunosuppressing patient from highly endemic areas

ArthropodScabies Malignancy, transplant immunosuppression, AIDS Leads to ‘Norwegian’ or crusted scabies with widespread Mileno, 1998;

antineoplastic therapy, involvement by thick, crusted lesions. Sometimes has severe itching. Markell, 1999 Patient has numerous mites and is therefore highly contagious. Often less responsive to therapy

AIDS = acquired immunodeficiency syndrome; CNS = central nervous system.

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