Psychiatric Aspects of Infectious Diseases


Psychiatric symptoms can be associated with several systemic and central nervous system infections and they can be the initial presenting symptoms, occurring in the absence of neurological symptoms in some disorders as in some cases of viral encephalitis. They could also be part of the clinical picture in other cases such as psychosis or mood symptoms secondary to brucellosis or toxoplasmosis. Late-onset neuropsychiatric complications may also occur several years following the infection such as in the case of subacute sclerosing panencephalitis due to measles. Some Infectious diseases may have possible etiological role for major psychiatric disorders, based on yet unconfirmed reports for viral infectious diseases (e.g. Influenza virus and HSV-1) which are thought to have risk for developing schizophrenia and psychosis. Neuropsychiatric adverse effects can occur due to drugs (e.g. mefloquine, interferon-alpha) that are used for treatment of infectious diseases. Psychiatric symptoms can also be reactivated resulting from chronic, complicated and serious infections such as HIV that can lead to depression, anxiety or adjustment disorders, although CNS involvement can also be a possible etiological factor. Patients suffering from primary and severe psychiatric disorders are at increased risk of contracting infection; that is mainly related to high risk behaviors in patients with mania or schizophrenia. It is also important to consider that the co-occurrence of psychiatric symptoms and infection can be incidental (i.e. infectious diseases can occur in psychiatric patients regardless of the above mentioned factors). Early identification of the underlying etiology for organic/secondary psychiatric symptoms is essential for appropriate intervention and early treatment of the primary condition that could be the etiology of psychiatric symptoms so as to avoid unnecessary long-term psychiatric treatment and to avoid complications of possible misdiagnosis or delayed diagnosis of the primary condition.

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Mufaddel, A. , Omer, A. and Salem, M. (2014) Psychiatric Aspects of Infectious Diseases. Open Journal of Psychiatry, 4, 202-217. doi: 10.4236/ojpsych.2014.43027.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Nicolson, G.L. and Haier, J. (2009) Role of Chronic Bacterial and Viral Infections in Neurodegenerative, Neurobehavioral, Psychiatric, Autoimmune and Fatiguing Illnesses: Part 1. BJMP, 2, 20-28.
[2] Marsland, A.L., Bachen, E.A., Cohen, S., Rabin, B. and Manuck, S.B. (2002) Stress, Immune Reactivity and Susceptibility to Infectious Disease. Physiology and Behavior, 77, 711-716.
[3] DE Hert, M., Correl, C.U. Bobes, J., et al. (2011) Physical Illness in Patients with Severe Mental Disorders. I. Prevalence, Impact of Medications and Disparities in Health Care. World psychiatry, 10, 52-77.
[4] Rothbard, A.B., Blank, M.B., Staab, J.P., Have, T.T., Young, D.S., Berry, S.D. and Eachus, S. (2009) Previously Undetected Metabolic Syndromes and Infectious Diseases among Psychiatric Inpatients. Psychiatric Services, 60, 534-537.
[5] (2006) Chapter 14. In: Gelder, M., Harrison, P. and Cowen, P., Eds., Shorter Oxford Textbook of Psychiatry, 5th Edition, Oxford University Press, Oxford, 321-357.
[6] (1993) The International classification of Diseases (ICD-10)-Classification of Mental and Behavioral Disorders. WHO, Geneva, 1-267.
[7] Levenson, J.L. (2011) Infectious Diseases. In: Levenson, J.L. Ed., American Psychiatric Association Publishing Textbook of Psychosomatic Medicine, American Psychiatric Publishing, Washington DC, 615-635.
[8] Awadalla, A., Arikawa, H. and Templer, D.I. (1998) The Nature and Structure of Febrile Psychosis in the Sudan. Journal of Orthomolecular Medicine, 13, 136-138.
[9] Markham, J.A. and Koenig, J.I. (2011) Prenatal Stress: Role in Psychotic and Depressive Diseases. Psychopharmacology, 214, 89-106.
[10] Meyer, U. and Feldon, J. (2009) Neural Basis of Psychosis-Related Behavior in the Infection Model of Schizophrenia. Behavioural Brain Research, 204, 322-334.
[11] Buka, S.L., Tsuang, M.T., Torrey, E.F., Klebanoff, M.A., Bernstein, D. and Yolken, R.H. (2001) Maternal Infections and Subsequent Psychosis among Offspring. Archives of General Psychiatry, 58, 1032-1037.
[12] Brown, A.S., Begg, M.D., Gravenstein, S., et al. (2004) Serologic Evidence of Prenatal Influenza in the Etiology of Schizophrenia. Archives of General Psychiatry, 61, 774-780.
[13] Allebeck, P., Gunnell, D. and Harrison, G., et al. (2008) Infections in the CNS during Childhood and the Risk of Subsequent Psychotic Illness: A Cohort Study of More Than One Million Swedish Subjects. American Journal of Psychiatry, 165, 59-65.
[14] Leask, S.J. and Done, D.J. (2002) Adult Psychosis, Common Childhood Infections and Neurological Soft Signs in a National Birth Cohort. The British Journal of Psychiatry, 181, 387-392.
[15] Sorensen, H.J., Mortensen, E.L., Reinisch, J.M. and Mednick, S.A. (2009) Association between Prenatal Exposure to Bacterial Infection and Risk of Schizophrenia. Schizophrenia Bulletin, 35, 631-637.
[16] Gilmore, J.H. and Jarskog, L.F. (1997) Exposure to Infection and Brain Development: Cytokines in the Pathogenesis of Schizophrenia. Schizophrenia Research, 24, 365-367.
[17] Rantakallio, P., Jones, P., Moring, J. and Von Wendt, L. (1997) Association between Central Nervous System Infection during Childhood and Adult Onset Schizophrenia and Other Psychoses: A 28 Year Follow-Up. International Journal of Epidemiology, 26, 837-843.
[18] Kumar, P. and Clark, M. (2005) Clinical Medicine. 6th Edition, Chapter 2, Elsevier Saunders, Pheladeliphia, 19-152.
[19] Kitchener, N. (2005) Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). International Journal of Child Neuropsychiatry, 2, 195-202.
[20] Levenson, J.L. (2006) Psychiatric Issues in Infectious Diseases. Primary Psychiatry, 13, 29-32.
[21] Swedo, S.E., Leonard, H.L., Garvey, M., Mittleman, B., Allen, A.J., Perlmutter, S., Lougee, L., Dow, S., Zamkoff, J. and Dubbert, B.K. (1998) Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections: Clinical Description of the First 50 Cases. American Journal of Psychiatry, 155, 264-271.
[22] Victor, A.M. and Bernstein, G.A. (2009) Anxiety Disorders and Posttraumatic Stress Disorder Update. Psychiatric Clinics of North America, 32, 57-69.
[23] Mell, L.K., Davis, R.L. and Owens, D. (2005) Association between Streptococcal Infection and Obsessive-Compulsive Disorder, Tourette’s Syndrome, and Tic Disorder. Pediatrics, 116, 56-60.
[24] Lin, H., Williams, K.A., Katsovich, L., Findley, D.B., Grantz, H., Lombroso, P.J., et al. (2010) Streptococcal Upper Respiratory Tract Infections and Psychosocial Stress Predict Future Tic and Obsessive Compulsive Symptom Severity in Children and Adolescents with Tourette Syndrome and Obsessive-Compulsive Disorder. Biological Psychiatry, 67, 684-691.
[25] Sinder, L.A., Lougee, L., Slattery, M., Grant, P. and Swedo, S.E. (2005) Antibiotic Prophylaxis with Azithromycin or Penicillin for Childhood-Onset Neuropsychiatric Disorders. Biological Psychiatry, 57, 788-792.
[26] Moor, S. and Skrine, H. (1989) Psychosis in Mycoplasma Infection. Postgraduate Medical Journal, 65, 96-97.
[27] Narita, M. (2009) Pathogenesis of Neurologic Manifestations of Mycoplasma pneumoniae Infection. Pediatric Neurology, 41, 159-166.
[28] Koskiniemi, M. (1993) CNS Manifestations Associated with Mycoplasma pneumoniae Infections: Summary of Cases at the University of Helsinki and Review. Clinical Infectious Diseases, 17, S52-S57.
[29] Banerjee, B. and Petersen, K. (2009) Psychosis Following Mycoplasma pneumonia. Military Medicine, 174, 1001-1004.
[30] Candler, P.M. and Dale, R.L. (2004) Three Cases of Central Nervous System Complications Associated with Mycoplasma pneumoniae. Pediatric Neurology, 31, 133-138.
[31] Auvichayapat, N., Auvichayapat, P., Watanatorn, J., Thamaroj, J. and Jitpimolmard, S. (2006) Kluver-Bucy Syndrome after Mycoplasmal Bronchitis. Epilepsy & Behavior, 8, 320-322.
[32] Daxbeck, F. (2006) Mycoplasma pneumoniae Central Nervous System Infections. Current Opinion in Neurology, 19, 374-378.
[33] Chou, C.L., Lin, Y.J., Sheu, Y.L., Lin, C.J. and Hseuh, H. (2008) Persistent Klüver-Bucy Syndrome after Bilateral Temporal Lobe Infarction. Acta Neurologica Taiwanica, 17, 199-202.
[34] Hildenbrand, P., Craven, D.E., Jones, R. and Nemeskal, P. (2009) Lyme Neuroborreliosis: Manifestations of a Rapidly Emerging Zoonosis. AJNR American Journal of Neuroradiology, 30, 1079-1087.
[35] Fallon, B.A. and Nields, J.A. (1994) Lyme Disease: A Neuropsychiatric Illness. American Journal of Psychiatry, 151, 1571-1583.
[36] Hurley, R.A. and Taber, K.H. (2008) Acute and Chronic Lyme Disease: Controversies for Neuropsychiatry. Journal of Neuropsychiatry, 20, 4-6.
[37] Nicolson, G.L. and Haier, J. (2010) Role of Chronic Bacterial and Viral Infections in Neurodegenerative, Neurobehavioral, Psychiatric, Autoimmune and Fatiguing Illnesses: Part 2. British Journal of Medical Practitioners, 3, 301.
[38] Straight, T.M. and Martin, G.J. (2002) Current Treatment Options in Infectious Diseases. Current Science Inc., 4, 447-456.
[39] Tuncel, D., Ucmak, H., Gokce, M. and Utku, U. (2008) Neurobrucellosis. European Journal of General Medicine, 5, 245-248.
[40] Karsen, H., Akdeniz, H., Karahocagil, M.K., Irmak, H. and Sunnetcioglu, M. (2007) Toxic-Febrile Neurobrucellosis, Clinical Findings and Outcome of Treatment of Four Cases Based on Our Experience. Scandinavian Journal of Infectious Diseases, 39, 990-995.
[41] Shehata, G.A., Abdel-Baky, L., Rashed, H. and Elamin, H. (2010) Neuropsychiatric Evaluation of Patients with Brucellosis. Journal of NeuroVirology, 16, 48-55.
[42] Reitan, R.M. (1953) Intellectual and Affective Functions in Chronic Brucellosis. American Journal of Psychiatry, 110, 19-28.
[43] Webster, J.P., Lamberton, P.H.L., Donnelly, C.A. and Torrey, E.F. (2006) Parasites as Causative Agents of Human Affective Disorders? The Impact of Anti-Psychotic, Mood-Stabilizer and Anti-Parasite Medication on Toxoplasma gondii’s Ability to Alter Host Behavior. Proceedings of the Royal Society B: Biological Sciences, 273, 1023-1030.
[44] Alvarado-Esquivel, C., Alanis-Quinones, O.P., Arreola-Valenzuela, M.á., Rodríguez-Briones, A., Piedra-Nevarez, L.J., Duran-Morales, E., Estrada-Martínez, S., Martinez-García, S.A. and Liesenfeld, O. (2006) Seroepidemiology of Toxoplasma gondii Infection in Psychiatric Inpatients in a Northern Mexican City. BMC Infectious Diseases, 6, 178.
[45] Torrey, E.F. and Yolken, R.H. (2003) Toxoplasma gondii and Schizophrenia. Emerging Infectious Diseases, 9, 1375-1380.
[46] Arendt, G., Von Giesen, H.J., Hefter, H., Neuen-Jacob, E., Roick, H. and Jablonowski, H. (1999) Long-Term Course and Outcome in AIDs Patients with Cerebral Toxoplasmosis. Acta Neurologica Scandinavica, 100, 178-184.
[47] Henriquez, S.A., Brett, R., Alexander, J., Pratt, J. and Roberts, C.W. (2009) Neuropsychiatric Disease and Toxoplasma gondii Infection. NeuroImmunomodulation, 16, 122-133.
[48] Alvarado-Esquivel, C., Urbina-álvarez, J.D., Estrada-Martínez, S., Torres-Castorena, A., Molotla-de-León, G., Liesenfeld, O. and Dubey, J.P. (2011) Toxoplasma gondii Infection and Schizophrenia: A Case Control Study in a Low Toxoplasma Seroprevalence Mexican Population. Parasitology International, 60, 151-155.
[49] Tedla, Y., Shibre, T., Ali, O., Tadele, G., Woldeamanuel, Y., Asrat, D., Aseffa, A., Mihret, W., Abebe, M., Alem, A., Medhin, G. and Habte, A. (2011) Serum Antibodies to Toxoplasma gondii and Herpesvidae Family Viruses in Individuals with Schizophrenia and Bipolar Disorder: A Case-Control Study. Ethiopian Medical Journal, 49, 211-220.
[50] Webster, J.P., Lamberton, P.H.L., Donnelly, C.A. and Torrey, E.F. (2006) Parasites as Causative Agents of Human Affective Disorders? The Impact of Anti-Psychotic, Mood-Stabilizer and Anti-Parasite Medication on Toxoplasma gondii’s Ability to Alter Host Behavior. Proceedings of the Royal Society B: Biological Sciences, 273, 1023-1030.
[51] Webster, J.P. (2007) The Effect of Toxoplasma gondii on Animal Behavior: Playing Cat and Mouse. Schizophrenia Bulletin, 33, 752-756.
[52] Adamec, R.E., Burton, P., Shallow, T. and Budgell, J. (1999) NMDA Receptors Mediate Lasting Increases in Anxiety-Like Behavior Produced by the Stress of Predator Exposure—Implications for Anxiety Associated with Posttraumatic Stress Disorder. Physiology & Behavior, 65, 723-737.
[53] Blanchard, R.J., Blanchard, D.C., Rodgers, J. and Weiss, S.M. (1990) The Characterization and Modelling of Antipredator Defensive Behavior. Neuroscience & Biobehavioral Reviews, 14, 463-472.
[54] Castelli, F., Odolini, S., Autino, B., Foca, E. and Russo, R. (2010) Malaria Prophylaxis: A Comprehensive Review. Pharmaceuticals, 3, 3212-3239.
[55] Dondorp, A.M. (2005) Pathophysiology, Clinical Presentation and Treatment of Cerebral Malaria. Neurology Asia, 10, 67-77.
[56] Kumar, D., Patel, N., Pradeep, P., Surti, M.M. and Agarwal, S.B. (2003) Clinical Manifestations of Complicated Malaria—An Overview. JIACM, 4, 323-331.
[57] Idro, R., March, K., John, C.C. and Newton, C.R.J. (2010) Cerebral Malaria: Mechanism of Brain Injury and Strategies for Improved Neurocognitive Outcome. Pediatric Research, 68, 267-274.
[58] Telgt, D.S. (2005) Serious Psychiatric Symptoms after Chloroquine Treatment Following Experimental Malaria Infection. The Annals of Pharmacotherapy, 39, 551-554.
[59] Wooltorton, E. (2002) Mefloquine: Contraindicated in Patients with Mood, Psychotic or Seizure Disorders. Canadian Medical Association Journal, 176, 1147.
[60] Ronn, A.M., Ronne-Rasmussen, J., Gotzsce, P.C. and Bygbjerg, I.C. (1998) Neuropsychiatric Manifestations after Mefloquine Therapy for Plasmodium falciparum Malaria: Comparing a Retrospective and a Prospective Study. Tropical Medicine and International Health, 3, 83-88.
[61] Tran, T.M., Browning, J. and Dell, M.L. (2006) Psychosis with Paranoid Delusions after Atherapeutic Dose of Mefloquine: A Case Report. Malaria Journal, 5, 74.
[62] Garg, P., Mody, P. and Lall, K.B. (1990) Toxic Psychosis Due to Chloroquine-Not Uncommon in Children. Clinical Pediatrics, 29, 448-450.
[63] Chadwick, D.R. (2005) Viral Meningitis. British Medical Bulletin, 75-76, 1-14.
[64] Caroff, S.N., Mann, S.C., Glittoo, M.F., Sullivan, K.A. and Campbell, E.C. (2001) Psychiatric Manifestations of Acute Viral Encephalitis. Psychiatric Annals, 32, 193-204.
[65] Lakeman, F.D. and Whitley, R.J. (1995) Diagnosis of Herpes Simplex Encephalitis: Application of Polymerase Chain Reaction to Cerebrospinal Fluid from Brain-Biopsied Patients and Correlation with Disease. Journal of Infectious Diseases, 171, 857-863.
[66] Shirts, B.H., Prasad, K.M., Pogue-Geile, M.F., Dickerson, F., Yolken, R.H. and Nimgaonkar, V.L. (2008) Antibodies to Cytomegalovirus and Herpes Simplex Virus 1 Associated with Cognitive Function in Schizophrenia. Schizophrenia Research, 106, 268-274.
[67] Niebuhr, D.W., Millikan, A.M., Yolken, R., Li, Y. and Weber, N.S. (2007) Results from a Hypothesis Generating Case-Control Study: Herpes Family Viruses and Schizophrenia among Military Personnel. Schizophrenia Bulletin, 34, 1182-1188.
[68] Prasad, K.M., Eack, S.M., Goradia, D., Pancholi, K.M., Keshavan, M.S., Yolken, R.H. and Nimgaonkar, V.L. (2011) Progressive Gray Matter Loss and Changes in Cognitive Functioning Associated with Exposure to Herpes Simplex Virus 1 in Schizophrenia: A Longitudinal Study. American Journal of Psychiatry, 168, 822-830.
[69] Yolken, R.H., Torrey, E.F., Lieberman, J.A., Yang, S. and Dickerson, F.B. (2011) Serological Evidence of Exposure to Herpes Simplex Virus Type 1 Is Associated with Cognitive Deficits in the CATIE Schizophrenia Sample. Schizophrenia Research, 128, 61-65.
[70] Dickerson, F., Stallings, C., Sullens, A., Origoni, A., Leister, F., Krivogorsky, B. and Yolken, R. (2008) Association between Cognitive Functioning, Exposure to Herpes Simplex Virus Type 1, and the COMT Val158Met Genetic Polymorphism in Adults without a Psychiatric Disorder. Brain, Behavior, and Immunity, 22, 1103-1107.
[71] Davidson, S., Judd, F., Jolley, D., Hocking, B., Thompson, S. and Hyland, B. (2001) Risk Factors for HIV/AIDS and Hepatitis C among the Chronic Mentally Ill. Australian & New Zealand Journal of Psychiatry, 35, 203-209.
[72] Cournos, F. and McKinnon, K. (1997) HIV Seroprevalence among People with Severe Mental Illness in the United States: A Critical Review. Clinical Psychology Review, 17, 259-269.
[73] Dolder, C.R., Patterson, T.L. and Jeste, D.V. (2004) HIV, Psychosis and Aging: Past, Present and Future. AIDS, 18, 35-43.
[74] Goodkin, K. (2009) Psychiatric Aspects of HIV Spectrum Disease. FOCUS, 7, 303-310.
[75] Bing, E.G., Burnam, M.A., Longshore, D., Fleishman, J.A., Sherbourne, C.D., London, A.S., Turner, B.J., Eggan, F., Beckman, R., Vitiello, B., Morton, S.C., Orlando, M., Bozzette, S.A., Ortiz-Barron, L. and Shapiro, M. (2001) Psychiatric Disorders and Drug Use among Human Immunodeficiency Virus-Infected Adults in the United States. Archives of General Psychiatry, 58, 721-728.
[76] Tsao, J.C.I., Dobalian, A. and Naliboff, B.D. (2004) Panic Disorder and Pain in a National Sample of Persons Living with HIV. Pain, 109, 172-180.
[77] Nelligan, J.A., Loftis, J.M., Matthews, A.M., Zucker, B.L., Linke, A.M. and Hauser, P. (2008) Depression Comorbidity and Antidepressant Use in Veterans with Chronic Hepatitis C: Results from a Retrospective Chart Review. Journal of Clinical Psychiatry, 69, 810-816.
[78] Vignau, J., Karila, L., Costisella, O. and Canva, V. (2005) Hepatitis C, Interferon α and Depression: Main Physiopathologic Hypothesis. L’Encéphale, 31, 349-357.
[79] Fireman, M., Indest, D.W., Blackwell, A., Whitehead, A.J. and Hauser, P. (2005) Adressing Tri-Morbidity (Hepatitis C, Psychiatric Disorders and Substance Use): The Importance of Routine Mental Health Screening as a Component of a Comanagement Model of Care. Clinical Infectious Diseases, 40, S286-S291.
[80] Sylvestre, D.L., Loftis, J.M., Hauser, P., Genser, S., Cesari, H., Borek, N., Kresina, T.F., Seeff, L. and Francis, H. (2004) Co-Occurring Hepatitis C, Substance Use, and Psychiatric Illness: Treatment Issues and Developing Integrated Models of Care. Journal of Urban Health, 81, 719-34.
[81] Wasay, M., Channa, R., Jumani, M., Shabbir, G., Azeemuddin, M. and Zafar, A. (2008) Encephalitis and Myelitis Associated with Dengue Viral Infection: Clinical and Neuroimaging Features. Clinical Neurology and Neurosurgery, 110, 635-640.
[82] Domingues, R.B., Kuster, G.W., Onuki-Castro, F.L., Souza, V.A., Levi, J.E. and Pannuti, C.S. (2008) Involvement of the Central Nervous System in Patients with Dengue Virus Infection. Journal of the Neurological Sciences, 267, 36-40.
[83] Hunsperger, E.A. and Roehrig, J.T. (2006) Temporal Analyses of the Neuropathogenesis of a West Nile Virus Infection in Mice. Journal of NeuroVirology, 12, 129-139.
[84] Murray, K.O., Resnick, M. and Miller, V. (2007) Depression after Infection with West Nile Virus. Emerging Infectious Diseases, 13, 479-481.
[85] Watson, N.K., Bartt, R.E., Houff, S.A., Leurgans, S.E. and Schneck, M.J. (2005) Focal Neurological Deficits and West Nile Virus Infection. Clinical Infectious Diseases, 40, e59-e62.
[86] Hsu, P.C., Groer, M. and Beckie, T. (2014) New Findings: Depression, Suicide, and Toxoplasma gondii Infection. Journal of the American Association of Nurse Practitioners, Epub Ahead of Print.
[87] Xiao, J., Li, Y., Prandovszky, E., Karuppagounder, S.S., Talbot Jr., C.C., Dawson, V.L., Dawson, T.M. and Yolken, R.H. (2014) MicroRNA-132 Dysregulation in Toxoplasma gondii Infection Has Implications for Dopamine Signaling Pathway. Neuroscience, 268, 128-138.
[88] Parlog, A., Harsan, L.A., Zagrebelsky, M., Weller, M., von Elverfeldt, D., Mawrin, C., Korte, M. and Dunay, I.R. (2014) Chronic Murine Toxoplasmosis Is Defined by Subtle Changes in Neuronal Connectivity. Disease Models & Mechanisms, 7, 459-469.
[89] Huckans, M., Fuller, B.E., Olavarria, H., Sasaki, A.W., Chang, M., Flora, K.D., Kolessar, M., Kriz, D., Anderson, J.R., Vandenbark, A.A. and Loftis, J.M. (2014) Multi-Analyte Profile Analysis of Plasma Immune Proteins: Altered Expression of Peripheral Immune Factors Is Associated with Neuropsychiatric Symptom Severity in Adults with and without Chronic Hepatitis C Virus Infection. Brain and Behavior, 4, 123-142.
[90] Cerejeira, J., Lagarto, L. and Mukaetova-Ladinska, E.B. (2014) The Immunology of Delirium. Neuroimmunomodulation, 21, 72-78.
[91] Ritchie, C.W., Newman, T.H., Leurent, B. and Sampson, E.L. (2014) The Association between C-Reactive Protein and Delirium in 710 Acute Elderly Hospital Admissions. International Psychogeriatrics, 26, 717-724.

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