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1. Treatment of Multisystem Inflammatory Syndrome in Children

Author

McArdle A. J., Vito O., Patel H., Seaby E. G., Shah P., Wilson C., Broderick C., Nijman R., Tremoulet A. H., Munblit D., Ulloa-Gutierrez R., Carter M. J., De T., Hoggart C., Whittaker E., Herberg J. A., Kaforou M., Cunnington A. J., Levin M., Vazquez J. A., Carmona R., Perez L., Rubinos M., Veliz N., Yori S., Haerynck F., Hoste L., Leal I. A., Da Silva A. R. A., Silva A. E. A., Barchik A., Barreiro S. T. A., Cochrane N., Teixeira C. H., Arauj J. M., Ossa R. A. P. -D. L., Vieira C. S., Dimitrova A., Ganeva M., Stefanov S., Telcharova-Mihaylovska A., Biggs C. M., Scuccimarri R., Withington D., Raul B. B., Ampuero C., Aravena J., Casanova D., Cruces P., Diaz F., Garcia-Salum T., Godoy L., Medina R. A., Galaz G. V., Avila-Aguero M. L., Brenes-Chacon H., Ivankovich-Escoto G., Yock-Corrales A., Badib A., Badreldin K., Elkhashab Y., Heshmat H., Heinonen S., Angoulvant F., Belot A., Ouldali N., Beske F., Heep A., Masjosthusmann K., Reiter K., Heuvel I. V. D., Both U. V., Agrafiotou A., Antachopoulos C., Eleftheriou I., Farmaki E., Fotis L., Kafetzis D., Lampidi S., Liakopoulou T., Maritsi D., Michailidou E., Milioudi M., Mparmpounaki I., Papadimitriou E., Papaevangelou V., Roilides E., Tsiatsiou O., Tsolas G., Tsolia M., Vantsi P., Pineda L. Y. B., Aguilar K. L. B., Quintero E. M. C., Ip P., Kwan M. Y. W., Kwok J., Lau Y. L., To K., Wong J. S. C., David M., Farkas D., Kalcakosz S., Szekeres K., Zsigmond B., Aslam N., Andreozzi L., Bianco F., Bucciarelli V., Buonsenso D., Cimaz R., D'Argenio P., Dellepiane R. M., Fabi M., Mastrolia M. V., Mauro A., Mazza A., Romani L., Simonini G., Tipo V., Valentini P., Verdoni L., Reel B., Pace D., Torpiano P., Flores M. F., Dominguez M. G., Vargas A. L. G., Hernandez L. L., Figueroa R. P. M., Gaxiola G. P., Valadez J., Klevberg S., Knudsen P. K., Maseide P. H., Carrera J. M., Castano E. G., Timana C. A. D., Leon T. D., Estripeaut D., Levy J., Norero X., Record J., Rojas-Bonilla M., Iramain R., Hernandez R., Huaman G., Munaico M., Peralta C., Seminario D., Yarleque E. H. Z., Gadzinska J., Mandziuk J., Okarska-Napierala M., Alacheva Z. A., Alexeeva E., Ananin P. V., Antsupova M., Bakradze M. D., Bobkova P., Borzakova S., Chashchina I. L., Fisenko A. P., Gautier M. S., Glazyrina A., Kondrikova E., Korobyants E., Korsunskiy A. A., Kovygina K., Krasnaya E., Kurbanova S., Kurdup M. K., Mamutova A. V., Mazankova L., Mitushin I. L., Nargizyan A., Orlova Y. O., Osmanov I. M., Polyakova A. S., Romanova O., Samitova E., Sologub A., Spiridonova E., Tepaev R. F., Tkacheva A. A., Yusupova V., Zholobova E., Grasa C. D., Segura N. L., Martinon-Torres F., Melendo S., Echevarria A. M., Guzman J. M. M., Argueta J. R. P., Rivero-Calle I., Riviere J., Rodriguez-Gonzalez M., Rojo P., Manubens J. S., Soler-Palacin P., Soriano-Arandes A., Tagarro A., Villaverde S., Altman M., Brodin P., Horne A., Palmblad K., Brotschi B., Sauteur P. M., Schmid J. P., Prader S., Relly C., Schlapbach L. J., Seiler M., Truck J., Wutz D., Ketharanathan N., Vermont C., Ozkan E. A., Erdeniz E. H., Borisova G., Boychenko L., Diudenko N., Kasiyan O., Katerynych K., Melnyk K., Miagka N., Teslenko M., Trykosh M., Volokha A., Akomolafe T., Al-Abadi E., Alders N., Avram P., Bamford A., Bank M., Roy R. B., Beattie T., Boleti O., Broad J., Carrol E. D., Chandran A., Cooper H., Davies P., Emonts M., Evans C., Fidler K., Foster C., Gong C., Gongrun B., Gonzalez C., Grandjean L., Grant K., Hacohen Y., Hall J., Hassell J., Hesketh C., Hewlett J., Hnieno A., Holt-Davis H., Hossain A., Hudson L. D., Johnson M., Johnson S., Jyothish D., Kampmann B., Kavirayani A., Kelly D., Kucera F., Langer D., Lillie J., Longbottom K., Lyall H., MacKdermott N., Maltby S., McLelland T., McMahon A. -M., Miller D., Morrison Z., Mosha K., Muller J., Myttaraki E., Nadel S., Osaghae D., Osman F., Ostrzewska A., Panthula M., Papachatzi E., Papadopoulou C., Penner J., Polandi S., Prendergast A. J., Ramnarayan P., Rhys-Evans S., Riordan A., Rodrigues C. M. C., Romaine S., Seddon J., Shingadia D., Srivastava A., Struik S., Taylor A., Tran S., Tudor-Williams G., Van Der Velden F., Ventilacion L., Wellman P. A., Yanney M. P., Yeung S., Badheka A., Badran S., Bailey D. M., Burch A. K., Burns J. C., Cichon C., Cirks B., Dallman M. D., Delany D. R., Fairchok M., Friedman S., Geracht J., Langs-Barlow A., Mann K., Padhye A., Quade A., Ramirez K. A., Rockett J., Sayed I. A., Shahin A. A., Umaru S., Widener R., Angela M. H., Kandawasvika G., McArdle A.J., Vito O., Patel H., Seaby E.G., Shah P., Wilson C., Broderick C., Nijman R., Tremoulet A.H., Munblit D., Ulloa-Gutierrez R., Carter M.J., De T., Hoggart C., Whittaker E., Herberg J.A., Kaforou M., Cunnington A.J., Levin M., Vazquez J.A., Carmona R., Perez L., Rubinos M., Veliz N., Yori S., Haerynck F., Hoste L., Leal I.A., Da Silva A.R.A., Silva A.E.A., Barchik A., Barreiro S.T.A., Cochrane N., Teixeira C.H., Arauj J.M., Ossa R.A.P.-D.L., Vieira C.S., Dimitrova A., Ganeva M., Stefanov S., Telcharova-Mihaylovska A., Biggs C.M., Scuccimarri R., Withington D., Raul B.B., Ampuero C., Aravena J., Casanova D., Cruces P., Diaz F., Garcia-Salum T., Godoy L., Medina R.A., Galaz G.V., Avila-Aguero M.L., Brenes-Chacon H., Ivankovich-Escoto G., Yock-Corrales A., Badib A., Badreldin K., Elkhashab Y., Heshmat H., Heinonen S., Angoulvant F., Belot A., Ouldali N., Beske F., Heep A., Masjosthusmann K., Reiter K., Heuvel I.V.D., Both U.V., Agrafiotou A., Antachopoulos C., Eleftheriou I., Farmaki E., Fotis L., Kafetzis D., Lampidi S., Liakopoulou T., Maritsi D., Michailidou E., Milioudi M., Mparmpounaki I., Papadimitriou E., Papaevangelou V., Roilides E., Tsiatsiou O., Tsolas G., Tsolia M., Vantsi P., Pineda L.Y.B., Aguilar K.L.B., Quintero E.M.C., Ip P., Kwan M.Y.W., Kwok J., Lau Y.L., To K., Wong J.S.C., David M., Farkas D., Kalcakosz S., Szekeres K., Zsigmond B., Aslam N., Andreozzi L., Bianco F., Bucciarelli V., Buonsenso D., Cimaz R., D'Argenio P., Dellepiane R.M., Fabi M., Mastrolia M.V., Mauro A., Mazza A., Romani L., Simonini G., Tipo V., Valentini P., Verdoni L., Reel B., Pace D., Torpiano P., Flores M.F., Dominguez M.G., Vargas A.L.G., Hernandez L.L., Figueroa R.P.M., Gaxiola G.P., Valadez J., Klevberg S., Knudsen P.K., Maseide P.H., Carrera J.M., Castano E.G., Timana C.A.D., Leon T.D., Estripeaut D., Levy J., Norero X., Record J., Rojas-Bonilla M., Iramain R., Hernandez R., Huaman G., Munaico M., Peralta C., Seminario D., Yarleque E.H.Z., Gadzinska J., Mandziuk J., Okarska-Napierala M., Alacheva Z.A., Alexeeva E., Ananin P.V., Antsupova M., Bakradze M.D., Bobkova P., Borzakova S., Chashchina I.L., Fisenko A.P., Gautier M.S., Glazyrina A., Kondrikova E., Korobyants E., Korsunskiy A.A., Kovygina K., Krasnaya E., Kurbanova S., Kurdup M.K., Mamutova A.V., Mazankova L., Mitushin I.L., Nargizyan A., Orlova Y.O., Osmanov I.M., Polyakova A.S., Romanova O., Samitova E., Sologub A., Spiridonova E., Tepaev R.F., Tkacheva A.A., Yusupova V., Zholobova E., Grasa C.D., Segura N.L., Martinon-Torres F., Melendo S., Echevarria A.M., Guzman J.M.M., Argueta J.R.P., Rivero-Calle I., Riviere J., Rodriguez-Gonzalez M., Rojo P., Manubens J.S., Soler-Palacin P., Soriano-Arandes A., Tagarro A., Villaverde S., Altman M., Brodin P., Horne A., Palmblad K., Brotschi B., Sauteur P.M., Schmid J.P., Prader S., Relly C., Schlapbach L.J., Seiler M., Truck J., Wutz D., Ketharanathan N., Vermont C., Ozkan E.A., Erdeniz E.H., Borisova G., Boychenko L., Diudenko N., Kasiyan O., Katerynych K., Melnyk K., Miagka N., Teslenko M., Trykosh M., Volokha A., Akomolafe T., Al-Abadi E., Alders N., Avram P., Bamford A., Bank M., Roy R.B., Beattie T., Boleti O., Broad J., Carrol E.D., Chandran A., Cooper H., Davies P., Emonts M., Evans C., Fidler K., Foster C., Gong C., Gongrun B., Gonzalez C., Grandjean L., Grant K., Hacohen Y., Hall J., Hassell J., Hesketh C., Hewlett J., Hnieno A., Holt-Davis H., Hossain A., Hudson L.D., Johnson M., Johnson S., Jyothish D., Kampmann B., Kavirayani A., Kelly D., Kucera F., Langer D., Lillie J., Longbottom K., Lyall H., MacKdermott N., Maltby S., McLelland T., McMahon A.-M., Miller D., Morrison Z., Mosha K., Muller J., Myttaraki E., Nadel S., Osaghae D., Osman F., Ostrzewska A., Panthula M., Papachatzi E., Papadopoulou C., Penner J., Polandi S., Prendergast A.J., Ramnarayan P., Rhys-Evans S., Riordan A., Rodrigues C.M.C., Romaine S., Seddon J., Shingadia D., Srivastava A., Struik S., Taylor A., Tran S., Tudor-Williams G., Van Der Velden F., Ventilacion L., Wellman P.A., Yanney M.P., Yeung S., Badheka A., Badran S., Bailey D.M., Burch A.K., Burns J.C., Cichon C., Cirks B., Dallman M.D., Delany D.R., Fairchok M., Friedman S., Geracht J., Langs-Barlow A., Mann K., Padhye A., Quade A., Ramirez K.A., Rockett J., Sayed I.A., Shahin A.A., Umaru S., Widener R., Angela M.H., Kandawasvika G., Pediatric Surgery, Pediatrics, University of Zurich, National Institute of Health and Medical Research, Wellcome Trust, Medical Research Foundation, Shah, Priyen [0000-0001-9164-8862], Ulloa-Gutierrez, Rolando [0000-0002-9157-9227], Herberg, Jethro A [0000-0001-6941-6491], Cunnington, Aubrey J [0000-0002-1305-3529], Levin, Michael [0000-0003-2767-6919], and Apollo - University of Cambridge Repository

Subjects
Inotrope, Male, medicine.medical_treatment, 2700 General Medicine, 030204 cardiovascular system & hematology, Antibodies, Viral, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, Glucocorticoid, hemic and lymphatic diseases, Medicine and Health Sciences, 030212 general & internal medicine, Viral, Child, 11 Medical and Health Sciences, OUTCOMES, Respiration, Immunoglobulins, Intravenous, General Medicine, Systemic Inflammatory Response Syndrome, 3. Good health, Hospitalization, Treatment Outcome, Child, Preschool, Combination, Artificial, Regression Analysis, Drug Therapy, Combination, Female, Original Article, Intravenous, Life Sciences & Biomedicine, Cohort study, Human, medicine.medical_specialty, BATS Consortium, Adolescent, Immunoglobulins, 610 Medicine & health, Regression Analysi, Antibodies, Immunomodulation, 03 medical and health sciences, Medicine, General & Internal, Pharmacotherapy, Drug Therapy, Clinical Research, Internal medicine, General & Internal Medicine, medicine, MANAGEMENT, Confidence Intervals, Humans, Preschool, Propensity Score, Glucocorticoids, Mechanical ventilation, Science & Technology, business.industry, SARS-CoV-2, Inflammatory and immune system, COVID-19, Odds ratio, medicine.disease, Respiration, Artificial, Confidence interval, KAWASAKI-LIKE DISEASE, COVID-19 Drug Treatment, Systemic inflammatory response syndrome, 10036 Medical Clinic, Immunoglobulins, Intravenou, Propensity score matching, Cohort Studie, business, ACUTE RESPIRATORY SYNDROME, Confidence Interval, TOXIC-SHOCK-SYNDROME
Abstract

BackgroundEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.MethodsWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.ResultsData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.ConclusionsWe found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).

Published
2021

2. Treatment of Multisystem Inflammatory Syndrome in Children

Author

McArdle, A.J. Vito, O. Patel, H. Seaby, E.G. Shah, P. Wilson, C. Broderick, C. Nijman, R. Tremoulet, A.H. Munblit, D. Ulloa-Gutierrez, R. Carter, M.J. De, T. Hoggart, C. Whittaker, E. Herberg, J.A. Kaforou, M. Cunnington, A.J. Levin, M. Vazquez, J.A. Carmona, R. Perez, L. Rubinos, M. Veliz, N. Yori, S. Haerynck, F. Hoste, L. Leal, I.A. Da Silva, A.R.A. Silva, A.E.A. Barchik, A. Barreiro, S.T.A. Cochrane, N. Teixeira, C.H. Arauj, J.M. Ossa, R.A.P.-D.L. Vieira, C.S. Dimitrova, A. Ganeva, M. Stefanov, S. Telcharova-Mihaylovska, A. Biggs, C.M. Scuccimarri, R. Withington, D. Raul, B.B. Ampuero, C. Aravena, J. Casanova, D. Cruces, P. Diaz, F. Garcia-Salum, T. Godoy, L. Medina, R.A. Galaz, G.V. Avila-Aguero, M.L. Brenes-Chacon, H. Ivankovich-Escoto, G. Yock-Corrales, A. Badib, A. Badreldin, K. Elkhashab, Y. Heshmat, H. Heinonen, S. Angoulvant, F. Belot, A. Ouldali, N. Beske, F. Heep, A. Masjosthusmann, K. Reiter, K. Heuvel, I.V.D. Both, U.V. Agrafiotou, A. Antachopoulos, C. Eleftheriou, I. Farmaki, E. Fotis, L. Kafetzis, D. Lampidi, S. Liakopoulou, T. Maritsi, D. Michailidou, E. Milioudi, M. Mparmpounaki, I. Papadimitriou, E. Papaevangelou, V. Roilides, E. Tsiatsiou, O. Tsolas, G. Tsolia, M. Vantsi, P. Pineda, L.Y.B. Aguilar, K.L.B. Quintero, E.M.C. Ip, P. Kwan, M.Y.W. Kwok, J. Lau, Y.L. To, K. Wong, J.S.C. David, M. Farkas, D. Kalcakosz, S. Szekeres, K. Zsigmond, B. Aslam, N. Andreozzi, L. Bianco, F. Bucciarelli, V. Buonsenso, D. Cimaz, R. D'Argenio, P. Dellepiane, R.M. Fabi, M. Mastrolia, M.V. Mauro, A. Mazza, A. Romani, L. Simonini, G. Tipo, V. Valentini, P. Verdoni, L. Reel, B. Pace, D. Torpiano, P. Flores, M.F. Domínguez, M.G. Vargas, A.L.G. Hernandez, L.L. Figueroa, R.P.M. Gaxiola, G.P. Valadez, J. Klevberg, S. Knudsen, P.K. Maseide, P.H. Carrera, J.M. Castano, E.G. Timana, C.A.D. Leon, T.D. Estripeaut, D. Levy, J. Norero, X. Record, J. Rojas-Bonilla, M. Iramain, R. Hernandez, R. Huaman, G. Munaico, M. Peralta, C. Seminario, D. Yarleque, E.H.Z. Gadzinska, J. Mandziuk, J. Okarska-Napierała, M. Alacheva, Z.A. Alexeeva, E. Ananin, P.V. Antsupova, M. Bakradze, M.D. Bobkova, P. Borzakova, S. Chashchina, I.L. Fisenko, A.P. Gautier, M.S. Glazyrina, A. Kondrikova, E. Korobyants, E. Korsunskiy, A.A. Kovygina, K. Krasnaya, E. Kurbanova, S. Kurdup, M.K. Mamutova, A.V. Mazankova, L. Mitushin, I.L. Nargizyan, A. Orlova, Y.O. Osmanov, I.M. Polyakova, A.S. Romanova, O. Samitova, E. Sologub, A. Spiridonova, E. Tepaev, R.F. Tkacheva, A.A. Yusupova, V. Zholobova, E. Grasa, C.D. Segura, N.L. Martinon-Torres, F. Melendo, S. Echevarria, A.M. Guzman, J.M.M. Argueta, J.R.P. Rivero-Calle, I. Riviere, J. Rodriguez-Gonzalez, M. Rojo, P. Manubens, J.S. Soler-Palacin, P. Soriano-Arandes, A. Tagarro, A. Villaverde, S. Altman, M. Brodin, P. Horne, A. Palmblad, K. Brotschi, B. Sauteur, P.M. Schmid, J.P. Prader, S. Relly, C. Schlapbach, L.J. Seiler, M. Truck, J. Wutz, D. Ketharanathan, N. Vermont, C. Ozkan, E.A. Erdeniz, E.H. Borisova, G. Boychenko, L. Diudenko, N. Kasiyan, O. Katerynych, K. Melnyk, K. Miagka, N. Teslenko, M. Trykosh, M. Volokha, A. Akomolafe, T. Al-Abadi, E. Alders, N. Avram, P. Bamford, A. Bank, M. Roy, R.B. Beattie, T. Boleti, O. Broad, J. Carrol, E.D. Chandran, A. Cooper, H. Davies, P. Emonts, M. Evans, C. Fidler, K. Foster, C. Gong, C. Gongrun, B. Gonzalez, C. Grandjean, L. Grant, K. Hacohen, Y. Hall, J. Hassell, J. Hesketh, C. Hewlett, J. Hnieno, A. Holt-Davis, H. Hossain, A. Hudson, L.D. Johnson, M. Johnson, S. Jyothish, D. Kampmann, B. Kavirayani, A. Kelly, D. Kucera, F. Langer, D. Lillie, J. Longbottom, K. Lyall, H. MacKdermott, N. Maltby, S. McLelland, T. McMahon, A.-M. Miller, D. Morrison, Z. Mosha, K. Muller, J. Myttaraki, E. Nadel, S. Osaghae, D. Osman, F. Ostrzewska, A. Panthula, M. Papachatzi, E. Papadopoulou, C. Penner, J. Polandi, S. Prendergast, A.J. Ramnarayan, P. Rhys-Evans, S. Riordan, A. Rodrigues, C.M.C. Romaine, S. Seddon, J. Shingadia, D. Srivastava, A. Struik, S. Taylor, A. Taylor, A. Taylor, A. Tran, S. Tudor-Williams, G. Van Der Velden, F. Ventilacion, L. Wellman, P.A. Yanney, M.P. Yeung, S. Badheka, A. Badran, S. Bailey, D.M. Burch, A.K. Burns, J.C. Cichon, C. Cirks, B. Dallman, M.D. Delany, D.R. Fairchok, M. Friedman, S. Geracht, J. Langs-Barlow, A. Mann, K. Padhye, A. Quade, A. Ramirez, K.A. Rockett, J. Sayed, I.A. Shahin, A.A. Umaru, S. Widener, R. Angela, M.H. Kandawasvika, G. BATS Consortium

Subjects
hemic and lymphatic diseases
Abstract

BACKGROUND Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. METHODS We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation. RESULTS Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups. CONCLUSIONS We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. Copyright © 2021 Massachusetts Medical Society.

Published
2021

3. Impact of KDM6B mosaic brain knockout on synaptic function and behavior.

Author

Brauer B, Ancatén-González C, Ahumada-Marchant C, Meza RC, Merino-Veliz N, Nardocci G, Varela-Nallar L, Arriagada G, Chávez AE, and Bustos FJ

Subjects
Animals, Mice, Brain metabolism, Neuronal Plasticity genetics, Behavior, Animal, Hippocampus metabolism, Epigenesis, Genetic, Male, Synapses metabolism, Jumonji Domain-Containing Histone Demethylases genetics, Jumonji Domain-Containing Histone Demethylases metabolism, Mice, Knockout, Synaptic Transmission genetics, Autism Spectrum Disorder genetics
Abstract

Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions., (© 2024. The Author(s).)

Published
2024
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4. Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior.

Author

Ahumada-Marchant C, Ancatén-Gonzalez C, Haensgen H, Brauer B, Merino-Veliz N, Droste R, Arancibia F, Horvitz HR, Constantine-Paton M, Arriagada G, Chávez AE, and Bustos FJ

Subjects
Animals, Mice, Behavior, Animal physiology, Brain metabolism, Neurons metabolism, Neurons physiology, Synapses metabolism, Synapses physiology, Synaptic Transmission, Vacuolar Proton-Translocating ATPases metabolism, Vacuolar Proton-Translocating ATPases genetics, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Mice, Knockout, Synaptic Vesicles metabolism
Abstract

Background: The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown., Results: To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments., Conclusions: We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions., (© 2024. The Author(s).)

Published
2024
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5. Identification and expression analysis of two steamer-like retrotransposons in the Chilean blue mussel (Mytilus chilensis).

Author

Arriagada G, Quezada J, Merino-Veliz N, Avilés F, Tapia-Cammas D, Gomez J, Curotto D, Valdes JA, Oyarzún PA, Gallardo-Escárate C, Metzger MJ, and Alvarez M

Subjects
Animals, Chile, Mytilus genetics, Retroelements genetics
Abstract

Background: Disseminated neoplasia (DN) is a proliferative cell disorder of the circulatory system of bivalve mollusks. The disease is transmitted between individuals and can also be induced by external chemical agents such as bromodeoxyuridine. In Mya arenaria, we have cloned and characterized an LTR-retrotransposon named Steamer. Steamer mRNA levels and gene copy number correlates with DN and can be used as a marker of the disease. So far, the only mollusk where a retrotransposon expression relates to DN is Mya arenaria. On the other hand, it has been reported that the Chilean blue mussel Mytilus chilensis can also suffers DN. Our aim was to identify retrotransposons in Mytilus chilensis and to study their expression levels in the context of disseminated neoplasia., Results: Here we show that 7.1% of individuals collected in August 2018, from two farming areas, presents morphological characteristics described in DN. Using Steamer sequence to interrogate the transcriptome of M. chilensis we found two putative retrotransposons, named Steamer-like elements (MchSLEs). MchSLEs are present in the genome of M. chilensis and MchSLE1 is indeed an LTR-retrotransposon. Neither expression, nor copy number of the reported MchSLEs correlate with DN status but both are expressed at different levels among individual animals. We also report that in cultured M. chilensis haemocytes MchSLEs1 expression can be induced by bromodeoxyuridine., Conclusions: We conclude that SLEs present in Mytilus chilensis are differentially expressed among individuals and do not correlate with disseminated neoplasia. Treatment of haemocytes with a stressor like bromodeoxyuridine induces expression of MchSLE1 suggesting that in Mytilus chilensis environmental stressors can induce activation of LTR-retrotransposon., (© 2024. The Author(s).)

Published
2024
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6. KMT2C knockout generates ASD-like behaviors in mice.

Author

Brauer B, Merino-Veliz N, Ahumada-Marchant C, Arriagada G, and Bustos FJ

Abstract

Neurodevelopmental disorders have been associated with genetic mutations that affect cellular function, including chromatin regulation and epigenetic modifications. Recent studies in humans have identified mutations in KMT2C, an enzyme responsible for modifying histone tails and depositing H3K4me1 and H3K4me3, as being associated with Kleefstra syndrome 2 and autism spectrum disorder (ASD). However, the precise role of KMT2C mutations in brain disorders remains poorly understood. Here we employed CRISPR/Cas9 gene editing to analyze the effects of KMT2C brain specific knockout on animal behavior. Knocking out KMT2C expression in cortical neurons and the mouse brain resulted in decreased KMT2C levels. Importantly, KMT2C brain specific knockout animals exhibited repetitive behaviors, social deficits, and intellectual disability resembling ASD. Our findings shed light on the involvement of KMT2C in neurodevelopmental processes and establish a valuable model for elucidating the cellular and molecular mechanisms underlying KMT2C mutations and their relationship to Kleefstra syndrome 2 and ASD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brauer, Merino-Veliz, Ahumada-Marchant, Arriagada and Bustos.)

Published
2023
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7. Mechanistic Analysis of the VirA Sensor Kinase in Agrobacterium tumefaciens Using Structural Models.

Author

Swackhammer A, Provencher EAP, Donkor AK, Garofalo J, Dowling S, Garchitorena K, Phyo A, Ramírez Veliz N, Karen M, Kwon A, Diep R, Norris M, Safo MK, and Pierce BD

Abstract

Agrobacterium tumefaciens pathogenesis of plants is initiated with signal reception and culminates with transforming the genomic DNA of its host. The histidine sensor kinase VirA receives and reacts to discrete signaling molecules for the full induction of the genes necessary for this process. Though many of the components of this process have been identified, the precise mechanism of how VirA coordinates the response to host signals, namely phenols and sugars, is unknown. Recent advances of molecular modeling have allowed us to test structure/function predictions and contextualize previous experiments with VirA. In particular, the deep mind software AlphaFold has generated a structural model for the entire protein, allowing us to construct a model that addresses the mechanism of VirA signal reception. Here, we deepen our analysis of the region of VirA that is critical for phenol reception, model and probe potential phenol-binding sites of VirA, and refine its mechanism to strengthen our understanding of A. tumefaciens signal perception., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Swackhammer, Provencher, Donkor, Garofalo, Dowling, Garchitorena, Phyo, Ramírez Veliz, Karen, Kwon, Diep, Norris, Safo and Pierce.)

Published
2022
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8. Multisystem Inflammatory Syndrome Temporally Related to COVID-19 in Children From Latin America and the Caribbean Region: A Systematic Review With a Meta-Analysis of Data From Regional Surveillance Systems.

Author

Ruvinsky S, Voto C, Roel M, Fustiñana A, Veliz N, Brizuela M, Rodriguez S, Ulloa-Gutierrez R, and Bardach A

Abstract

Background: With the emergence of the COVID-19 pandemic, increasing numbers of cases of the multisystem inflammatory syndrome in children (MIS-C) have been reported worldwide; however, it is unclear whether this syndrome has a differential pattern in children from Latin America and the Caribbean (LAC). We conducted a systematic review and meta-analysis to analyze the epidemiological, clinical, and outcome characteristics of patients with MIS-C in LAC countries., Methods: A systematic literature search was conducted in the main electronic databases and scientific meetings from March 1, 2020, to June 30, 2021. Available reports on epidemiological surveillance of countries in the region during the same period were analyzed., Results: Of the 464 relevant studies identified, 23 were included with 592 patients with MIS-C from LAC. Mean age was 6.6 years (IQR, 6-7.4 years); 60% were male. The most common clinical manifestations were fever, rash, and conjunctival injection; 59% showed Kawasaki disease. Pool proportion of shock was 52%. A total of 47% of patients were admitted to the pediatric intensive care unit (PICU), 23% required mechanical ventilation, and 74% required vasoactive drugs. Intravenous gamma globulin alone was administered in 87% of patients, and in combination with steroids in 60% of cases. Length of hospital stay was 10 days (IQR, 9-10) and PICU stay 5.75 (IQR, 5-6). Overall case fatality ratio was 4% and for those hospitalized in the PICU it was 7%., Conclusion: Limited information was available on the clinical outcomes. Improvements in the surveillance system are required to obtain a better epidemiologic overview in the region., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ruvinsky, Voto, Roel, Fustiñana, Veliz, Brizuela, Rodriguez, Ulloa-Gutierrez and Bardach.)

Published
2022
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9. Pediatric Inflammatory Multisystem Syndrome Associated With SARS-CoV-2: A Retrospective Cohort Study From Argentina.

Author

Rosanova MT, Perez G, Katsicas MM, Arias AP, Picollo M, Palladino M, Gonzalez C, Veliz N, Buchovsky A, Lede R, and Bologna R

Subjects
Argentina epidemiology, Child, Child, Preschool, Humans, Retrospective Studies, SARS-CoV-2, Systemic Inflammatory Response Syndrome, COVID-19
Abstract

Objective: To evaluate the differential characteristics of SARS-COV-2 associated inflammatory multisystem syndrome (MIS-C) in children., Methods: A retrospective cohort study was conducted.  The definition of MIS- C was based on WHO criteria. Temporally related COVID-19 patients were included as controls., Results: 25 patients with MIS-C and 75 controls were included. Multivariate multiple logistic regression model of variables that showed to be significant in univariate analysis revealed that age ≥2 years (OR 24.7; 95% CI 1.03 -592.4; P=0.048), lymphopenia (OR 9.03, 95%CI 2.05-39.7; P=0.004), and platelet count <150x109/L (OR 11.7; 95% CI 1.88-75.22; P=0.009) were significantly associated with MIS-C. Presence of underlying disease seemed to reduce the risk of MIS-C (OR 0.06; 95% CI 0.01-0.3)., Conclusions: MIS-C was more common in patients older than 2 years and in those with lymphopenia or thrombocytopenia. Underlying disease appears to reduce the risk of MIS-C.

Published
2021

10. [Streptococcus pneumoniae endocarditis in a child: a case report].

Author

Escarrá F, Fedullo AG, Veliz N, Rosa J, Oribe R, Di Santo M, Reijtman BV, Mastroianni LA, and Pérez G

Subjects
Child, Preschool, Humans, Male, Endocarditis, Bacterial diagnosis, Pneumococcal Infections diagnosis
Abstract

Introduction: the incidence of invasive infections caused by pneumococcus (Streptococcus pneumoniae) has declined since generalized vaccination with pneumococcal conjugated vaccine, but it is still a prevalent pathogen in children. Amongst pneumococcal invasive infections, IE (infectious endocarditis) is rare, with an incidence between 1 and 7%., Case Report: We describe the case of a previously healthy 4 year old boy, who had received one dose of 10-valent pneumococcal conjugate vaccine who presents with fever, a new heart murmur and heart failure. Blood cultures were posi tive for penicillin susceptible pneumococcus. The transthoracic echocardiogram showed tricuspid and pulmonary valve vegetations. The patient received 4 weeks of antibiotic treatment for pneumo-coccal IE. He presented secondary valve damage that needed surgical treatment., Conclusions: IE should be considered as a differential diagnosis of children presenting with fever and a newly diag nosed heart murmur, and pneumococcus as an etiologic agent in non hospitalized febrile patients with severe infections.

Published
2017
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