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5. STROKE VOLUME VARIATION AS AN INDEX OF FLUID RESPONSIVENESS CAN BE IMPAIRED BY MENTAL STRESS.

Author

WISZT, R., CZIPPELOVA, B., KROHOVA, J. CERNANOVA, MAZGUTOVA, N., TURIANIKOVA, Z., LAZAROVA, Z., and JAVORKA, M.

Subjects
PSYCHOLOGICAL stress, SINUS arrhythmia, BLOOD pressure, FLUIDS, PLETHYSMOGRAPHY, MENTAL arithmetic, THIRST
Abstract

Cardiac stroke volume variation (SVV) measurement is one of the techniques to detect fluid-responsive hypovolemia in patients under mechanical ventilation. There is an ongoing effort to apply SVV for this purpose also in conscious patients. However, the effect of mental stress often occurring in conscious patients as a potential confounding factor on SVV is not known. The aim of our study was to compare effect of simulated hypovolemia and mental stress on SVV in healthy volunteers in the context of potential confounders - breathing pattern, respiratory sinus arrhythmia magnitude and sex. We examined 102 young healthy volunteers (58 females), mean age 18.6 years. Finger arterial blood pressure was recorded by volume-clamp photoplethysmographic method (Finometer Pro, FMS, Amsterdam, Netherland). From the blood pressure curve, a built in Model Flow algorithm calculated stroke volume values (SV) for each heartbeat. Respiratory volume was recorded using calibrated respiratory inductive plethysmography (RespiTrace, NIMS, Miami Beach, FL, USA). During four phases of examination protocol (supine rest, head-up tilt (HUT), supine recovery, mental arithmetic task (MA)) we analyzed SVV related to respiratory activity. While during HUT we found an expected increase in SVV together with mean SV decrease, SVV significantly decreased during MA. The observed changes during MA could be attributed to an increased respiratory rate and/or decreased respiratory sinus arrhythmia. Sex related differences in SVV responses to HUT and MA were observed. We conclude that mental stress together with respiratory sinus arrhythmia and respiratory pattern changes can significantly influence SVV as a potential index of fluid responsiveness in conscious patients. [ABSTRACT FROM AUTHOR]

Published
2022
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7. Predicting outcome after traumatic brain injury: Practical prognostic models based on large cohort of international patients

Author

Perel, P. A., Olldashi, F., Muzha, I., Filipi, N., Lede, R., Copertari, P., Traverso, C., Copertari, A., Vergara, E. A., Montenegro, C., De Huidobro, R. R., Saladino, P., Surt, K., Cialzeta, J., Lazzeri, S., Pinero, G., Ciccioli, F., Videtta, W., Barboza, M. F., Svampa, S., Sciuto, V., Domeniconi, G., Bustamante, M., Waschbusch, M., Gullo, M. P., Drago, D. A., Linares, J. C. A., Camputaro, L., Troccoli, G., Galimberti, H., Tallott, M., Eybner, C., Buchinger, W., Fitzal, S., Mazairac, G., Oleffe, V., Grollinger, T., Delvaux, P., Carlier, L., Braet, V., Jacques, J. -M., De Knoop, D., Nasi, L., Choi, H. K., Schmitt, M., Gentil, A., Nacul, F., Barrios, P. B., Xinkang, C., Hua, L. S., Tian, H. H., Xiaodong, C., Gualteros, W., Otero, A. A., Arango, M., Ciro, J., Jaramillo, H., Gonzalez, I., Gomez, C., Arias, A., Fonseca, M., Mora, C., Cabrera, E. G. L., Betancurth, J. L., Munoz, P., Quinonez, J. A., Castillo, M. E. G., Lopez, O., Yepes, R. P., Cuellar, D. L., Paez, G., Chaves, H. D., Ordonez, P. E., Plata, Riccardo, Pineda, M., Pulido, L. E., Jaramillo, J. S. V., Rebolledo, C., Palma, O., Soler, C., Pastrana, I., Falero, R., Perera, M. D., Garcia, A. A., Oliva, R., Delgado, H. L., Carnero, A. M., Lopez, B. L., Gallardo, A. L., Morales, A. O., Lezcano, H., Ferrer, M. I., Bess, I. Z., Canino, G. R., Ruiz, E. M. P., Cruz, O. G., Svoboda, P., Kantorova, I., Ochmann, J., Scheer, P., Kozumplik, L., Marsova, J., Edelmann, K., Chytra, I., Bosman, R., Andrejsova, H., Pachl, J., Burger, J., Kramar, F., Ulloa, M. I., Gonzalez, L., Daccach, A., Ortega, A., Cevallos, S., Cueva, B. Z., Ochoa, M., Tapia, J. V., Hurtado, J., Wong, M. C. S., Santos, R., Khamis, H., Abaza, A. H., Fekry, A., El Kordy, S., Shawky, T., El-Sayed, H., Khalil, N., Negm, N., Fisal, S., Alamin, M., Shokry, H., Elhusseny, A. Y., Radwan, A., Rashid, M., Gogichaisvili, T., Ingorokva, G., Gongadze, N., Otarashvili, A., Kleist, W., Kalkum, M., Ulrich, P., Andrews, N., Nakos, G., Karavelis, A., Archontakis, G., Myrianthefs, P., Yadav, Y., Yadav, S., Khatri, R., Baghel, A., Husain, M., Jha, D., Chhang, W. H., Dhandhania, M., Fonning, C., Iyengar, S. N., Gupta, S., Ravi, R. R., Bopiah, K. S., Herur, A., Venkataramana, N. K., Satish, A., Bhavadasan, K., Morris, R., Ramesh, S., Dewan, Y., Singh, Y., Bhagchandani, R., Bhagchandani, S., Sethurayar, V. U., Ipe, S., Sreekumar, G., Panigrahi, M., Reddy, A., Khosla, V., Pillay, H., Thomas, N., Sridhar, K., Jose, B., Kurian, N., Praharaj, S., Pillai, S., Ramana, Kiyawat, D., Maheshwari, K., Panikar, D., Chawla, J., Shenoy, S., Raja, A., Rupayana, Y., Reddy, S., Mohan, N., Kelkar, S., Johri, M., Golden, N., Maliawan, S., Fauzi, A., Farouk, U., Fakharian, E., Aramesh, A., Eghtedari, M., Ahmadzadeh, F., Gholami, A., Plunkett, P., Redican, C., Mcmahon, G., Annetta, Maria Giuseppina, Mouchaty, H., Bruzzone, E., Harding, B., Qureshi, M., Idris, Z., Jafri Abdullah, N. C., Ghazali, G., Ghani, A. R. I., Cheah, F., Cabrera, A., Gonzalez, J. L. M., Loria-Castellanos, J., Jackson, S., Hutchinson, R., Komolafe, E., Adeolu, A., Komolafe, M., Adeyemi-Doro, O., Bankole, F., Shehu, B., Danlami, V., Odebode, O., Oluwadiya, K., Sanni, A., Giebel, H., Kumar, S., Jooma, R., Mezquita, J. E., Ovelar, C. O., Portillo, M. G., Rodriguez, D., Balica, L., Oprita, B., Sklerniacof, M., Steflea, L., Bandut, L., Danil, A., Iliescu, R., Ciurea, J., El-Dawlatly, A., Alwatidy, S., Al-Yafi, W., El-Dawlatly, M., Krunic-Protic, R., Janosevic, V., Tan, J., Seah, C., Trenkler, S., Humenansky, M., Stajancova, T., Schwendt, I., Laincz, A., Julius, Z., Maros, S., Firment, J., Cifranicova, M., Saniova, B., Kalig, K., Medekova, S., Wiszt, R., Macuga, I., Hartzenberg, B., Du Plessis, G., Houlie, Z., Nathoo, N., Khumalo, S., Tracey, R., Munoz-Sanchez, A., Francisco Murillo-Cabezas, N. C., Flores-Cordero, J., Rincon- Ferrari, D., Rubi, M., Caler, L., Del Campo, M. M., Laguna, L. B., Nava, J. M., Minguillon, M. A., Lopez, A. M., Ramos-Gomez, L., De La Torre-Prados, V., Pellejero, R., Laloe, V., Mandrella, B., Suganthan, Perera, S., Mahendran, K., Stocker, R., Ludwig, S., Zimmermann, H., Denzler, U., Yutthakasemsunt, S., Kittiwattanagul, W., Piyavechvirat, P., Tapsai, P., Namuang-Jan, A., Chantapimpa, U., Watanachai, C., Subsompon, P., Pussanakawatin, W., Khunjan, P., Tangchitvittaya, S., Nilapong, S., Klangsang, T., Taechakosol, W., Srinat, A., Jerbi, Z., Borsali- Falfoul, N., Rezgui, M., Cakar, N., Ssenyonjo, H., Kobusingye, O., Lomas, G., Yates, D., Lecky, F., Bleetman, A., Baldwin, A., Jenkinson, E., Pantrini, S., Stewart, J., Contractor, N., Roberts, T., Butler, J., Pinto, A., Lee, D., Brayley, N., Robbshaw, K., Dix, C., Graham, S., Pye, S., Green, M., Kellins, A., Moulton, C., Fogg, B., Cottingham, R., Funnell, S., Shanker, U., Summers, C., Malek, L., Ashcroft, C., Powell, J., Moore, S., Buckley, S., Grocutt, M., Chambers, S., Morrice, A., Marshall, H., Harris, J., Matthews, W., Tippet, J., Mardell, S., Macmillan, F., Shaw, A., Luthra, P., Dixon, G., Ahmed, M., Young, M., Mason, S., Loveday, I., Clark, C., Taylor, S., Wilson, P., Ali, K., Greenwood, S., White, M., Perez, R., Eljamel, S., Wasserberg, J., Shale, H., Read, C., Mccarron, J., Pennell, A., Ray, G., Thurston, J., Brown, E., Jaffey, L., Graves, M., Bailey, R., Loveridge, N., Evans, G., Hughes, S., Ahmed, M. K., Richardson, J., Gallagher, C., Odedun, T., Lees, K., Foley, D., Payne, N., Pennycook, A., Griffiths, C., Moore, D., Byrne, D., Dasan, S., Banerjee, Abhishek, Mcguinness, S., Chikhani, C., Zoltie, N., Barlow, I., Stell, I., Hulse, W., Crossley, J., Watkins, L., Dorani, B., Van Viet, T., Plata R., Annetta M. G. (ORCID:0000-0001-7574-1311), Banerjee A., Perel, P. A., Olldashi, F., Muzha, I., Filipi, N., Lede, R., Copertari, P., Traverso, C., Copertari, A., Vergara, E. A., Montenegro, C., De Huidobro, R. R., Saladino, P., Surt, K., Cialzeta, J., Lazzeri, S., Pinero, G., Ciccioli, F., Videtta, W., Barboza, M. F., Svampa, S., Sciuto, V., Domeniconi, G., Bustamante, M., Waschbusch, M., Gullo, M. P., Drago, D. A., Linares, J. C. A., Camputaro, L., Troccoli, G., Galimberti, H., Tallott, M., Eybner, C., Buchinger, W., Fitzal, S., Mazairac, G., Oleffe, V., Grollinger, T., Delvaux, P., Carlier, L., Braet, V., Jacques, J. -M., De Knoop, D., Nasi, L., Choi, H. K., Schmitt, M., Gentil, A., Nacul, F., Barrios, P. B., Xinkang, C., Hua, L. S., Tian, H. H., Xiaodong, C., Gualteros, W., Otero, A. A., Arango, M., Ciro, J., Jaramillo, H., Gonzalez, I., Gomez, C., Arias, A., Fonseca, M., Mora, C., Cabrera, E. G. L., Betancurth, J. L., Munoz, P., Quinonez, J. A., Castillo, M. E. G., Lopez, O., Yepes, R. P., Cuellar, D. L., Paez, G., Chaves, H. D., Ordonez, P. E., Plata, Riccardo, Pineda, M., Pulido, L. E., Jaramillo, J. S. V., Rebolledo, C., Palma, O., Soler, C., Pastrana, I., Falero, R., Perera, M. D., Garcia, A. A., Oliva, R., Delgado, H. L., Carnero, A. M., Lopez, B. L., Gallardo, A. L., Morales, A. O., Lezcano, H., Ferrer, M. I., Bess, I. Z., Canino, G. R., Ruiz, E. M. P., Cruz, O. G., Svoboda, P., Kantorova, I., Ochmann, J., Scheer, P., Kozumplik, L., Marsova, J., Edelmann, K., Chytra, I., Bosman, R., Andrejsova, H., Pachl, J., Burger, J., Kramar, F., Ulloa, M. I., Gonzalez, L., Daccach, A., Ortega, A., Cevallos, S., Cueva, B. Z., Ochoa, M., Tapia, J. V., Hurtado, J., Wong, M. C. S., Santos, R., Khamis, H., Abaza, A. H., Fekry, A., El Kordy, S., Shawky, T., El-Sayed, H., Khalil, N., Negm, N., Fisal, S., Alamin, M., Shokry, H., Elhusseny, A. Y., Radwan, A., Rashid, M., Gogichaisvili, T., Ingorokva, G., Gongadze, N., Otarashvili, A., Kleist, W., Kalkum, M., Ulrich, P., Andrews, N., Nakos, G., Karavelis, A., Archontakis, G., Myrianthefs, P., Yadav, Y., Yadav, S., Khatri, R., Baghel, A., Husain, M., Jha, D., Chhang, W. H., Dhandhania, M., Fonning, C., Iyengar, S. N., Gupta, S., Ravi, R. R., Bopiah, K. S., Herur, A., Venkataramana, N. K., Satish, A., Bhavadasan, K., Morris, R., Ramesh, S., Dewan, Y., Singh, Y., Bhagchandani, R., Bhagchandani, S., Sethurayar, V. U., Ipe, S., Sreekumar, G., Panigrahi, M., Reddy, A., Khosla, V., Pillay, H., Thomas, N., Sridhar, K., Jose, B., Kurian, N., Praharaj, S., Pillai, S., Ramana, Kiyawat, D., Maheshwari, K., Panikar, D., Chawla, J., Shenoy, S., Raja, A., Rupayana, Y., Reddy, S., Mohan, N., Kelkar, S., Johri, M., Golden, N., Maliawan, S., Fauzi, A., Farouk, U., Fakharian, E., Aramesh, A., Eghtedari, M., Ahmadzadeh, F., Gholami, A., Plunkett, P., Redican, C., Mcmahon, G., Annetta, Maria Giuseppina, Mouchaty, H., Bruzzone, E., Harding, B., Qureshi, M., Idris, Z., Jafri Abdullah, N. C., Ghazali, G., Ghani, A. R. I., Cheah, F., Cabrera, A., Gonzalez, J. L. M., Loria-Castellanos, J., Jackson, S., Hutchinson, R., Komolafe, E., Adeolu, A., Komolafe, M., Adeyemi-Doro, O., Bankole, F., Shehu, B., Danlami, V., Odebode, O., Oluwadiya, K., Sanni, A., Giebel, H., Kumar, S., Jooma, R., Mezquita, J. E., Ovelar, C. O., Portillo, M. G., Rodriguez, D., Balica, L., Oprita, B., Sklerniacof, M., Steflea, L., Bandut, L., Danil, A., Iliescu, R., Ciurea, J., El-Dawlatly, A., Alwatidy, S., Al-Yafi, W., El-Dawlatly, M., Krunic-Protic, R., Janosevic, V., Tan, J., Seah, C., Trenkler, S., Humenansky, M., Stajancova, T., Schwendt, I., Laincz, A., Julius, Z., Maros, S., Firment, J., Cifranicova, M., Saniova, B., Kalig, K., Medekova, S., Wiszt, R., Macuga, I., Hartzenberg, B., Du Plessis, G., Houlie, Z., Nathoo, N., Khumalo, S., Tracey, R., Munoz-Sanchez, A., Francisco Murillo-Cabezas, N. C., Flores-Cordero, J., Rincon- Ferrari, D., Rubi, M., Caler, L., Del Campo, M. M., Laguna, L. B., Nava, J. M., Minguillon, M. A., Lopez, A. M., Ramos-Gomez, L., De La Torre-Prados, V., Pellejero, R., Laloe, V., Mandrella, B., Suganthan, Perera, S., Mahendran, K., Stocker, R., Ludwig, S., Zimmermann, H., Denzler, U., Yutthakasemsunt, S., Kittiwattanagul, W., Piyavechvirat, P., Tapsai, P., Namuang-Jan, A., Chantapimpa, U., Watanachai, C., Subsompon, P., Pussanakawatin, W., Khunjan, P., Tangchitvittaya, S., Nilapong, S., Klangsang, T., Taechakosol, W., Srinat, A., Jerbi, Z., Borsali- Falfoul, N., Rezgui, M., Cakar, N., Ssenyonjo, H., Kobusingye, O., Lomas, G., Yates, D., Lecky, F., Bleetman, A., Baldwin, A., Jenkinson, E., Pantrini, S., Stewart, J., Contractor, N., Roberts, T., Butler, J., Pinto, A., Lee, D., Brayley, N., Robbshaw, K., Dix, C., Graham, S., Pye, S., Green, M., Kellins, A., Moulton, C., Fogg, B., Cottingham, R., Funnell, S., Shanker, U., Summers, C., Malek, L., Ashcroft, C., Powell, J., Moore, S., Buckley, S., Grocutt, M., Chambers, S., Morrice, A., Marshall, H., Harris, J., Matthews, W., Tippet, J., Mardell, S., Macmillan, F., Shaw, A., Luthra, P., Dixon, G., Ahmed, M., Young, M., Mason, S., Loveday, I., Clark, C., Taylor, S., Wilson, P., Ali, K., Greenwood, S., White, M., Perez, R., Eljamel, S., Wasserberg, J., Shale, H., Read, C., Mccarron, J., Pennell, A., Ray, G., Thurston, J., Brown, E., Jaffey, L., Graves, M., Bailey, R., Loveridge, N., Evans, G., Hughes, S., Ahmed, M. K., Richardson, J., Gallagher, C., Odedun, T., Lees, K., Foley, D., Payne, N., Pennycook, A., Griffiths, C., Moore, D., Byrne, D., Dasan, S., Banerjee, Abhishek, Mcguinness, S., Chikhani, C., Zoltie, N., Barlow, I., Stell, I., Hulse, W., Crossley, J., Watkins, L., Dorani, B., Van Viet, T., Plata R., Annetta M. G. (ORCID:0000-0001-7574-1311), and Banerjee A.

Abstract

Objective: To develop and validate practical prognostic models for death at 14 days and for death or severe disability six months after traumatic brain injury. Design: Multivariable logistic regression to select variables that were independently associated with two patient outcomes. Two models designed: "basic" model (demographic and clinical variables only) and "CT" model (basic model plus results of computed tomography). The models were subsequently developed for high and low-middle income countries separately. Setting: Medical Research Council (MRC) CRASH Trial. Subjects: 10 008 patients with traumatic brain injury. Models externally validated in a cohort of 8509. Results: The basic model included four predictors: age, Glasgow coma scale, pupil reactivity, and the presence of major extracranial injury. The CT model also included the presence of petechial haemorrhages, obliteration of the third ventricle or basal cisterns, subarachnoid bleeding, midline shift, and non-evacuated haematoma. In the derivation sample the models showed excellent discrimination (C statistic above 0.80). The models showed good calibration graphically. The Hosmer-Lemeshow test also indicated good calibration, except for the CT model in low-middle income countries. External validation for unfavourable outcome at six months in high income countries showed that basic and CT models had good discrimination (C statistic 0.77 for both models) but poorer calibration. Conclusion: Simple prognostic models can be used to obtain valid predictions of relevant outcomes in patients with traumatic brain injury.

Published
2008

8. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): Randomised placebo-controlled trial

Author

Olldashi, F., Muzha, I., Filipi, N., Lede, R., Copertari, P., Traverso, C., Copertari, A., Vergara, E. A., Montenegro, C., De Huidobro, R. R., Surt, K., Cialzeta, J., Lazzeri, S., Pinero, G., Ciccioli, F., Videtta, W., Barboza, M. F., Svampa, S., Sciuto, V., Domeniconi, G., Bustamante, M., Waschbusch, M., Gullo, M. P., Drago, D. A., Linares, J. C. A., Camputaro, L., Troccoli, G., Galimberti, H., Tallott, M., Eybner, C., Buchinger, W., Fitzal, S., Mazairac, G., Oleffe, V., Grollinger, T., Delvaux, P., Carlier, L., Braet, V., Jacques, J. -M., De Knoop, D., Nasi, L., Choi, H. K., Schmitt, M., Gentil, A., Nacul, F., Barrios, P. B., Xinkang, C., Hua, L. S., Tian, H. H., Xiaodong, C., Gualteros, W., Otero, A. A., Arango, M., Ciro, J., Jaramillo, H., Garcia, G., Gonzalez, I., Gomez, C., Arias, A., Fonseca, M., Mora, C., Cabrera, E. G. L., Betancurth, J. L., Munoz, P., Quinonez, J. A., Castillo, M. E. G., Lopez, O., Yepes, R. P., Cuellar, D. L., Paez, G., Chaves, H. D., Ordonez, P. E., Plata, Riccardo, Pineda, M., Pulido, L. E., Jaramillo, J. S. V., Rebolledo, C., Palma, O., Soler, C., Pastrana, I., Falero, R., Perera, M. D., Garcia, A. A., Oliva, R., Delgado, H. L., Carnero, A. M., Lopez, B. L., Gallardo, A. L., Morales, A. O., Lezcano, H., Ferrer, M. I., Bess, I. Z., Canino, G. R., Ruiz, E. M. P., Cruz, O. G., Svoboda, P., Kantorova, I., Ochmann, J., Scheer, P., Kozumplik, L., Marsova, J., Edelmann, K., Chytra, I., Bosman, R., Andrejsova, H., Pachl, J., Burger, J., Kramar, F., Ulloa, M. I., Gonzalez, L., Daccach, A., Ortega, A., Cevallos, S., Cueva, B. Z., Ochoa, M., Tapia, J. V., Hurtado, J., Wong, M. C. S., Santos, R., Khamis, H., Abaza, A. H., Fekry, A., El Kordy, S., Shawky, T., El-Sayed, H., Khalil, N., Negm, N., Fisal, S., Shokry, H., Alamin, M., Elhusseny, A. Y., Radwan, A., Rashid, M., Gogichaisvili, T., Ingorokva, G., Gongadze, N., Otarashvili, A., Kleist, W., Kalkum, M., Ulrich, P., Andrews, N., Nakos, G., Karavelis, A., Archontakis, G., Myrianthefs, P., Yadav, Y., Yadav, S., Khatri, R., Baghel, A., Husain, M., Jha, D., Hoong Chhang, W., Dhandhania, M., Fonning, C., Iyengar, S. N., Gupta, S., Ravi, R. R., Bopiah, K. S., Herur, A., Venkataramana, N. K., Satish, A., Bhavadasan, K., Morris, R., Ramesh, S., Dewan, Y., Singh, Y., Bhagchandani, R., Bhagchandani, S., Sethurayar, V., Ipe, S., Sreekumar, G., Panigrahi, M., Reddy, A., Khosla, V., Pillay, H., Thomas, N., Sridhar, K., Jose, B., Kurian, N., Praharaj, S., Pillai, S., Ramana, Kiyawat, D., Maheshwari, K., Panikar, D., Chawla, J., Shenoy, S., Raja, A., Rupayana, Y., Reddy, S., Mohan, N., Kelkar, S., Johri, M., Golden, N., Maliawan, S., Fauzi, A., Farouk, U., Fakharian, E., Aramesh, A., Eghtedari, M., Ahmadzadeh, F., Gholami, A., Plunkett, P., Redican, C., Mcmahon, G., Annetta, Maria Giuseppina, Mouchaty, H., Bruzzone, E., Harding, B., Qureshi, M., Idris, Z., Abdullah, J., Ghazali, G., Ghani, A., Cheah, F., Gonzalez, J., Loria-Castellanos, J., Jackson, S., Hutchinson, R., Komolafe, E., Adeolu, A., Komolafe, M., Adeyemi-Doro, O., Bankole, F., Shehu, B., Danlami, V., Odebode, O., Oluwadiya, K., Sanni, A., Giebel, H., Kumar, S., Jooma, R., Mezquita, J., Ortiz Ovelar, C., Gonzales-Portillo, M., Rodriguez, D., Balica, L., Oprita, B., Sklerniacof, M., Steflea, L., Bandut, L., Danil, A., Iliescu, R., Ciurea, J., El-Dawlatly, A., Alwatidy, S., Al-Yafi, W., El-Dawlatly, M., Krunic-Protic, R., Janosevic, V., Tan, J., Seah, C., Trenkler, S., Humenansky, M., Stajancova, T., Schwendt, I., Laincz, A., Julius, Z., Maros, S., Firment, J., Cifranicova, M., Saniova, B., Kalig, K., Medekova, S., Wiszt, R., Macsuga, I., Hartzenberg, B., Du Plessis, G., Houlie, Z., Nathoo, N., Khumalo, S., Tracey, R., Munoz-Sanchez, A., Murillo-Cabezas, F., Flores-Cordero, J., Rincon-Ferrari, D., Rubi, M., Caler, L., Del Campo, M., Laguna, L., Manuel Nava, J., Minguillon, M., Lopez, A., Ramos-Gomez, L., De La Torre-Prados, V., Pellejero, R., Laloe, V., Mandrella, B., Suganthan, Perera, S., Mahendran, K., Stocker, R., Ludwig, S., Zimmermann, H., Denzler, U., Yutthakasemsunt, S., Kittiwattanagul, W., Watanachai, C., Subsompon, P., Pussanakawatin, W., Khunjan, P., Tangchitvittaya, S., Nilapong, S., Klangsang, T., Taechakosol, W., Srinat, A., Jerbi, Z., Borsali-Falfoul, N., Rezgui, M., Cakar, N., Ssenyonjo, H., Kobusingye, O., Lomas, G., Yates, D., Lecky, F., Bleetman, A., Baldwin, A., Jenkinson, E., Pantrini, S., Stewart, J., Contractor, N., Roberts, T., Butler, J., Pinto, A., Lee, D., Brayley, N., Robbshaw, K., Dix, C., Graham, S., Pye, S., Green, M., Kellins, A., Moulton, C., Fogg, B., Cottingham, R., Funnell, S., Shanker, U., Summers, C., Malek, L., Ashcroft, C., Powell, J., Moore, S., Buckley, S., Grocutt, M., Chambers, S., Morrice, A., Marshall, H., Harris, J., Matthews, W., Tippet, J., Mardell, S., Macmillan, F., Shaw, A., Luthra, P., Dixon, G., Ahmed, M., Young, M., Mason, S., Loveday, I., Clark, C., Taylor, S., Wilson, P., Ali, K., Greenwood, S., White, M., Perez, R., Eljamel, S., Wasserberg, J., Shale, H., Read, C., Mccarron, J., Pennell, A., Ray, G., Thurston, J., Brown, E., Jaffey, L., Graves, M., Bailey, R., Loveridge, N., Evans, G., Hughes, S., Richardson, J., Gallagher, C., Odedun, T., Lees, K., Foley, D., Payne, N., Pennycook, A., Griffiths, C., Moore, D., Byrne, D., Dasan, S., Banerjee, Abhishek, Mcguinness, S., Chikhani, C., Zoltie, N., Barlow, I., Stell, I., Hulse, W., Crossley, J., Watkins, L., Dorani, B., Vanviet, T., Saladino, P., Cabrera, A., Baigent, C., Bracken, M., Chadwick, D., Curley, K., Duley, L., Farrell, B., Haegi, M., Nickson, G., Peto, R., Pickard, J., Roberts, I., Sandercock, P., Teasdale, G., Collins, R., Haines, S., Macmahon, S., Warlow, C., Edwards, P., Ritchie, N., Shakur, H., Ramos, M., Barnetson, L., Fernandes, J., Tooth, D., Free, C., Narayanan, L., Collander, J., Abernethy, J., Bardswell, J., Mashru, R., Godward, C., Afolabi, L., Ritchie, A., Hosford, T., Collingwood, A., Massey, S., Plata R., Annetta M. (ORCID:0000-0001-7574-1311), Banerjee A., Olldashi, F., Muzha, I., Filipi, N., Lede, R., Copertari, P., Traverso, C., Copertari, A., Vergara, E. A., Montenegro, C., De Huidobro, R. R., Surt, K., Cialzeta, J., Lazzeri, S., Pinero, G., Ciccioli, F., Videtta, W., Barboza, M. F., Svampa, S., Sciuto, V., Domeniconi, G., Bustamante, M., Waschbusch, M., Gullo, M. P., Drago, D. A., Linares, J. C. A., Camputaro, L., Troccoli, G., Galimberti, H., Tallott, M., Eybner, C., Buchinger, W., Fitzal, S., Mazairac, G., Oleffe, V., Grollinger, T., Delvaux, P., Carlier, L., Braet, V., Jacques, J. -M., De Knoop, D., Nasi, L., Choi, H. K., Schmitt, M., Gentil, A., Nacul, F., Barrios, P. B., Xinkang, C., Hua, L. S., Tian, H. H., Xiaodong, C., Gualteros, W., Otero, A. A., Arango, M., Ciro, J., Jaramillo, H., Garcia, G., Gonzalez, I., Gomez, C., Arias, A., Fonseca, M., Mora, C., Cabrera, E. G. L., Betancurth, J. L., Munoz, P., Quinonez, J. A., Castillo, M. E. G., Lopez, O., Yepes, R. P., Cuellar, D. L., Paez, G., Chaves, H. D., Ordonez, P. E., Plata, Riccardo, Pineda, M., Pulido, L. E., Jaramillo, J. S. V., Rebolledo, C., Palma, O., Soler, C., Pastrana, I., Falero, R., Perera, M. D., Garcia, A. A., Oliva, R., Delgado, H. L., Carnero, A. M., Lopez, B. L., Gallardo, A. L., Morales, A. O., Lezcano, H., Ferrer, M. I., Bess, I. Z., Canino, G. R., Ruiz, E. M. P., Cruz, O. G., Svoboda, P., Kantorova, I., Ochmann, J., Scheer, P., Kozumplik, L., Marsova, J., Edelmann, K., Chytra, I., Bosman, R., Andrejsova, H., Pachl, J., Burger, J., Kramar, F., Ulloa, M. I., Gonzalez, L., Daccach, A., Ortega, A., Cevallos, S., Cueva, B. Z., Ochoa, M., Tapia, J. V., Hurtado, J., Wong, M. C. S., Santos, R., Khamis, H., Abaza, A. H., Fekry, A., El Kordy, S., Shawky, T., El-Sayed, H., Khalil, N., Negm, N., Fisal, S., Shokry, H., Alamin, M., Elhusseny, A. Y., Radwan, A., Rashid, M., Gogichaisvili, T., Ingorokva, G., Gongadze, N., Otarashvili, A., Kleist, W., Kalkum, M., Ulrich, P., Andrews, N., Nakos, G., Karavelis, A., Archontakis, G., Myrianthefs, P., Yadav, Y., Yadav, S., Khatri, R., Baghel, A., Husain, M., Jha, D., Hoong Chhang, W., Dhandhania, M., Fonning, C., Iyengar, S. N., Gupta, S., Ravi, R. R., Bopiah, K. S., Herur, A., Venkataramana, N. K., Satish, A., Bhavadasan, K., Morris, R., Ramesh, S., Dewan, Y., Singh, Y., Bhagchandani, R., Bhagchandani, S., Sethurayar, V., Ipe, S., Sreekumar, G., Panigrahi, M., Reddy, A., Khosla, V., Pillay, H., Thomas, N., Sridhar, K., Jose, B., Kurian, N., Praharaj, S., Pillai, S., Ramana, Kiyawat, D., Maheshwari, K., Panikar, D., Chawla, J., Shenoy, S., Raja, A., Rupayana, Y., Reddy, S., Mohan, N., Kelkar, S., Johri, M., Golden, N., Maliawan, S., Fauzi, A., Farouk, U., Fakharian, E., Aramesh, A., Eghtedari, M., Ahmadzadeh, F., Gholami, A., Plunkett, P., Redican, C., Mcmahon, G., Annetta, Maria Giuseppina, Mouchaty, H., Bruzzone, E., Harding, B., Qureshi, M., Idris, Z., Abdullah, J., Ghazali, G., Ghani, A., Cheah, F., Gonzalez, J., Loria-Castellanos, J., Jackson, S., Hutchinson, R., Komolafe, E., Adeolu, A., Komolafe, M., Adeyemi-Doro, O., Bankole, F., Shehu, B., Danlami, V., Odebode, O., Oluwadiya, K., Sanni, A., Giebel, H., Kumar, S., Jooma, R., Mezquita, J., Ortiz Ovelar, C., Gonzales-Portillo, M., Rodriguez, D., Balica, L., Oprita, B., Sklerniacof, M., Steflea, L., Bandut, L., Danil, A., Iliescu, R., Ciurea, J., El-Dawlatly, A., Alwatidy, S., Al-Yafi, W., El-Dawlatly, M., Krunic-Protic, R., Janosevic, V., Tan, J., Seah, C., Trenkler, S., Humenansky, M., Stajancova, T., Schwendt, I., Laincz, A., Julius, Z., Maros, S., Firment, J., Cifranicova, M., Saniova, B., Kalig, K., Medekova, S., Wiszt, R., Macsuga, I., Hartzenberg, B., Du Plessis, G., Houlie, Z., Nathoo, N., Khumalo, S., Tracey, R., Munoz-Sanchez, A., Murillo-Cabezas, F., Flores-Cordero, J., Rincon-Ferrari, D., Rubi, M., Caler, L., Del Campo, M., Laguna, L., Manuel Nava, J., Minguillon, M., Lopez, A., Ramos-Gomez, L., De La Torre-Prados, V., Pellejero, R., Laloe, V., Mandrella, B., Suganthan, Perera, S., Mahendran, K., Stocker, R., Ludwig, S., Zimmermann, H., Denzler, U., Yutthakasemsunt, S., Kittiwattanagul, W., Watanachai, C., Subsompon, P., Pussanakawatin, W., Khunjan, P., Tangchitvittaya, S., Nilapong, S., Klangsang, T., Taechakosol, W., Srinat, A., Jerbi, Z., Borsali-Falfoul, N., Rezgui, M., Cakar, N., Ssenyonjo, H., Kobusingye, O., Lomas, G., Yates, D., Lecky, F., Bleetman, A., Baldwin, A., Jenkinson, E., Pantrini, S., Stewart, J., Contractor, N., Roberts, T., Butler, J., Pinto, A., Lee, D., Brayley, N., Robbshaw, K., Dix, C., Graham, S., Pye, S., Green, M., Kellins, A., Moulton, C., Fogg, B., Cottingham, R., Funnell, S., Shanker, U., Summers, C., Malek, L., Ashcroft, C., Powell, J., Moore, S., Buckley, S., Grocutt, M., Chambers, S., Morrice, A., Marshall, H., Harris, J., Matthews, W., Tippet, J., Mardell, S., Macmillan, F., Shaw, A., Luthra, P., Dixon, G., Ahmed, M., Young, M., Mason, S., Loveday, I., Clark, C., Taylor, S., Wilson, P., Ali, K., Greenwood, S., White, M., Perez, R., Eljamel, S., Wasserberg, J., Shale, H., Read, C., Mccarron, J., Pennell, A., Ray, G., Thurston, J., Brown, E., Jaffey, L., Graves, M., Bailey, R., Loveridge, N., Evans, G., Hughes, S., Richardson, J., Gallagher, C., Odedun, T., Lees, K., Foley, D., Payne, N., Pennycook, A., Griffiths, C., Moore, D., Byrne, D., Dasan, S., Banerjee, Abhishek, Mcguinness, S., Chikhani, C., Zoltie, N., Barlow, I., Stell, I., Hulse, W., Crossley, J., Watkins, L., Dorani, B., Vanviet, T., Saladino, P., Cabrera, A., Baigent, C., Bracken, M., Chadwick, D., Curley, K., Duley, L., Farrell, B., Haegi, M., Nickson, G., Peto, R., Pickard, J., Roberts, I., Sandercock, P., Teasdale, G., Collins, R., Haines, S., Macmahon, S., Warlow, C., Edwards, P., Ritchie, N., Shakur, H., Ramos, M., Barnetson, L., Fernandes, J., Tooth, D., Free, C., Narayanan, L., Collander, J., Abernethy, J., Bardswell, J., Mashru, R., Godward, C., Afolabi, L., Ritchie, A., Hosford, T., Collingwood, A., Massey, S., Plata R., Annetta M. (ORCID:0000-0001-7574-1311), and Banerjee A.

Abstract

Background Corticosteroids have been used to treat head injuries for more than 30 years. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1-2%. The CRASH trial—a multicentre international collaboration—aimed to confirm or refute such an effect by recruiting 20 000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment. Methods 10 008 adults with head injury and a Glasgow coma score (GCS) of 14 or less within 8 h of injury were randomly allocated 48 h infusion of corticosteroids (methylprednisolone) or placebo. Primary outcomes were death within 2 weeks of injury and death or disability at 6 months. Prespecified subgroup analyses were based on injury severity (GCS) at randomisation and on time from injury to randomisation. Analysis was by intention to treat. Effects on outcomes within 2 weeks of randomisation are presented in this report. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN74459797. Findings Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21·1%] vs 893 [17·9%] deaths; relative risk 1·18 [95% CI 1·09-1·27]; p=0·0001). The relative increase in deaths due to corticosteroids did not differ by injury severity (p=0·22) or time since injury (p=0·05). Interpretation Our results show there is no reduction in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks is unclear.

Published
2004

10. Redundancy and synergy in interactions among basic cardiovascular oscillations

Author

Michal Javorka, Barbora Czippelova, Luca Faes, Radovan Wiszt, Zuzana Turianikova, Jana Krohova, Nikoleta Mazgutova, Javorka M., Krohova J., Czippelova B., Turianikova Z., Wiszt R., Mazgutova N., and Faes L.

Subjects
cardiovascular oscillations, Computer science, Settore ING-INF/06 - Bioingegneria Elettronica E Informatica, Complex network, Cardiovascular control, Neuroscience
Abstract

The cardiovascular control system comprises a complex network of various control mechanisms operating on many time scales resulting in complex and mutually interconnected output signals (e.g. heart rate, systolic and diastolic blood pressures). The analysis of these interconnections could noninvasively provide an information on the regulatory mechanisms involved in cardiovascular control and thus could be potentially applied to better characterize cardiovascular dysregulation in pathological conditions. Our study demonstrates that the strength of interactions among signals changes with the time scale and as a response to changed autonomic state (orthostasis compared to supine rest). Novel insight regarding the interaction between two signals (sources) when influencing a target (third) signal could be obtained by the information-theoretic analysis of sources' redundancy and synergy.

Published
2020

11. Selection of blood pressure signal for baroreflex analysis

Author

Michal Javorka, Nikoleta Mazgutova, Barbora Czippelova, Radovan Wiszt, Jana Krohova, Luca Faes, Zuzana Turianikova, Krohova J., Czippelova B., Turianikova Z., Wiszt R., Mazgutova N., Faes L., and Javorka M.

Subjects
Chronotropic, medicine.medical_specialty, Supine position, business.industry, RR interval, Low frequency band, Baroreflex, Blood pressure, medicine.anatomical_structure, Internal medicine, Settore ING-INF/06 - Bioingegneria Elettronica E Informatica, Cardiology, Vascular resistance, Medicine, cardiovascular diseases, business, circulatory and respiratory physiology
Abstract

This study aims to evaluate the strength of the causal coupling among systolic, mean and diastolic blood pressure (SBP, MBP and DBP) with heart period (RR interval) (evaluating cardiac chronotropic baroreflex arm) and peripheral vascular resistance (PVR) (evaluating vascular resistance baroreflex arm) in frequency domain using partial spectral decomposition method. We recorded beat-to-beat RR, SBP, MBP and DBP and PVR values in 39 volunteers during supine rest and head-up tilt. Our results showed that during supine rest the most dominant causal coupling was from DBP to RR in both low and high frequency bands and significantly decreased during orthostasis. The strength of spectral couplings characterized the vascular resistance baroreflex arm did not differ during supine rest in low frequency band and SBP $\rightarrow \mathbf{PVR}$ direction dominated during HUT in both frequency bands.

Published
2020

12. Information domain analysis of respiratory sinus arrhythmia mechanisms

Author

Michal Javorka, Barbora Czippelova, Zuzana Turianikova, Radovan Wiszt, Zuzana Lazarova, Jana Krohova, Luca Faes, Krohova J., Czippelova B., Turianikova Z., Lazarova Z., Wiszt R., Javorka M., and Faes L.

Subjects
Adult, Male, medicine.medical_specialty, Supine position, Adolescent, Physiology, Blood Pressure, 030204 cardiovascular system & hematology, Baroreflex, 03 medical and health sciences, Orthostatic vital signs, Electrocardiography, Young Adult, 0302 clinical medicine, Heart Rate, Internal medicine, Heart rate, medicine, Humans, Information measure, Photoplethysmography, business.industry, Head-up tilt, Cardio-respiratory coupling, Cardiorespiratory fitness, General Medicine, Respiratory Sinus Arrhythmia, Blood pressure, Cardiology, Breathing, Female, business, 030217 neurology & neurosurgery, Respiratory minute volume
Abstract

Ventilation related heart rate oscillations – respiratory sinus arrhythmia (RSA) – originate in human from several mechanisms. Two most important of them – the central mechanism (direct communication between respiratory and cardiomotor centers), and the peripheral mechanism (ventilation-associated blood pressure changes transferred to heart rate via baroreflex) have been described in previous studies. The major aim of this study was to compare the importance of these mechanisms in the generation of RSA non-invasively during various states by quantifying the strength of the directed interactions between heart rate, systolic blood pressure and respiratory volume signals. Seventy-eight healthy volunteers (32 male, age range: 16.02-25.77 years, median age: 18.57 years) participated in this study. The strength of mutual interconnections among the spontaneous beat-to-beat oscillations of systolic blood pressure (SBP), R-R interval (RR signal) and respiration (volume changes – RESP signal) was quantified during supine rest, orthostatic challenge (head-up tilt, HUT) and cognitive load (mental arithmetics, MA) using bivariate and trivariate measures of cardio-respiratory information transfer to separate baroreflex and nonbaroreflex (central) mechanisms. Our results indicate that both basic mechanisms take part in RSA generation in the intact cardiorespiratory control of human subjects. During orthostatic and mental challenges baroreflex based peripheral mechanism becomes more important.

Published
2019

13. Respiratory Sinus Arrhythmia Mechanisms in Young Obese Subjects.

Author

Javorka M, Krohova J, Czippelova B, Turianikova Z, Mazgutova N, Wiszt R, Ciljakova M, Cernochova D, Pernice R, Busacca A, and Faes L

Abstract

Autonomic nervous system (ANS) activity and imbalance between its sympathetic and parasympathetic components are important factors contributing to the initiation and progression of many cardiovascular disorders related to obesity. The results on respiratory sinus arrhythmia (RSA) magnitude changes as a parasympathetic index were not straightforward in previous studies on young obese subjects. Considering the potentially unbalanced ANS regulation with impaired parasympathetic control in obese patients, the aim of this study was to compare the relative contribution of baroreflex and non-baroreflex (central) mechanisms to the origin of RSA in obese vs. control subjects. To this end, we applied a recently proposed information-theoretic methodology - partial information decomposition (PID) - to the time series of heart rate variability (HRV, computed from RR intervals in the ECG), systolic blood pressure (SBP) variability, and respiration (RESP) pattern measured in 29 obese and 29 age- and gender-matched non-obese adolescents and young adults monitored in the resting supine position and during postural and cognitive stress evoked by head-up tilt and mental arithmetic. PID was used to quantify the so-called unique information transferred from RESP to HRV and from SBP to HRV, reflecting, respectively, non-baroreflex and RESP-unrelated baroreflex HRV mechanisms, and the redundant information transferred from (RESP, SBP) to HRV, reflecting RESP-related baroreflex RSA mechanisms. Our results suggest that obesity is associated: (i) with blunted involvement of non-baroreflex RSA mechanisms, documented by the lower unique information transferred from RESP to HRV at rest; and (ii) with a reduced response to postural stress (but not to mental stress), documented by the lack of changes in the unique information transferred from RESP and SBP to HRV in obese subjects moving from supine to upright, and by a decreased redundant information transfer in obese compared to controls in the upright position. These findings were observed in the presence of an unchanged RSA magnitude measured as the high frequency (HF) power of HRV, thus suggesting that the changes in ANS imbalance related to obesity in adolescents and young adults are subtle and can be revealed by dissecting RSA mechanisms into its components during various challenges., (Copyright © 2020 Javorka, Krohova, Czippelova, Turianikova, Mazgutova, Wiszt, Ciljakova, Cernochova, Pernice, Busacca and Faes.)

Published
2020
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14. Arterial Stiffness and Endothelial Function in Young Obese Patients - Vascular Resistance Matters.

Author

Czippelova B, Turianikova Z, Krohova J, Wiszt R, Lazarova Z, Pozorciakova K, Ciljakova M, and Javorka M

Subjects
Adolescent, Adult, Ankle Brachial Index, Atherosclerosis etiology, Blood Pressure, Case-Control Studies, Child, Female, Follow-Up Studies, Humans, Male, Prognosis, Young Adult, Atherosclerosis diagnosis, Hemodynamics, Obesity complications, Vascular Resistance, Vascular Stiffness
Abstract

Aim: Motivated by the paradoxical and differing results of the early atherosclerosis related indices - Cardio-Ankle Vascular Index (CAVI) reflecting arterial stiffness and Reactive Hyperemia Index (RHI) evaluating endothelium dependent flow-induced vasodilation - in obesity, we aimed to assess CAVI and RHI in obese adolescents and young adults in the context of differences in systemic vascular resistance (SVR)., Methods: We examined 29 obese (14f, 15.4 [12.3-18.5] y; BMI: 33.2±4.4 kg.m -2 ) and 29 non-obese gender and age matched adolescents and young adults (BMI: 21.02±2.3 kg.m -2 ). CAVI and RHI were measured using VaSera VS-1500 (Fukuda Denshi, Japan) and Endo-PAT 2000 (Itamar Medical, Israel), respectively. Hemodynamic measures were recorded using volume-clamp plethysmography (Finometer Pro, FMS, Netherlands) and impedance cardiography (CardioScreen 2000, Medis GmbH, Germany). SVR and sympathetic activity related indices - Velocity Index (VI) and Heather Index (HI), and LF SAP (spectral power in low frequency band of systolic blood pressure oscillations) were determined., Results: In obese group, CAVI (4.59±0.88 vs. 5.18±0.63, p=0.002) and its refined version CAVI 0 (6.46±1.39 vs.7.33±0.99, p=0.002) were significantly lower. No significant difference in RHI was found. SVR and sympathetic activity indices were all significantly lower in the obese group than in the non-obese group. RHI correlated positively with SVR (r=0.390, p=0.044) in obese subjects., Conclusion: Our results indicate that both indices used for the detection of early atherosclerotic changes are influenced by vascular tone. Vascular resistance could influence CAVI and RHI results impairing their interpretation.

Published
2019
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15. Towards understanding the complexity of cardiovascular oscillations: Insights from information theory.

Author

Javorka M, Krohova J, Czippelova B, Turianikova Z, Lazarova Z, Wiszt R, and Faes L

Subjects
Adolescent, Adult, Cardiovascular Physiological Phenomena, Electrocardiography, Female, Humans, Male, Young Adult, Blood Pressure physiology, Heart Rate physiology, Information Theory, Models, Cardiovascular, Signal Processing, Computer-Assisted
Abstract

Cardiovascular complexity is a feature of healthy physiological regulation, which stems from the simultaneous activity of several cardiovascular reflexes and other non-reflex physiological mechanisms. It is manifested in the rich dynamics characterizing the spontaneous heart rate and blood pressure variability (HRV and BPV). The present study faces the challenge of disclosing the origin of short-term HRV and BPV from the statistical perspective offered by information theory. To dissect the physiological mechanisms giving rise to cardiovascular complexity in different conditions, measures of predictive information, information storage, information transfer and information modification were applied to the beat-to-beat variability of heart period (HP), systolic arterial pressure (SAP) and respiratory volume signal recorded non-invasively in 61 healthy young subjects at supine rest and during head-up tilt (HUT) and mental arithmetics (MA). Information decomposition enabled to assess simultaneously several expected and newly inferred physiological phenomena, including: (i) the decreased complexity of HP during HUT and the increased complexity of SAP during MA; (ii) the suppressed cardiorespiratory information transfer, related to weakened respiratory sinus arrhythmia, under both challenges; (iii) the altered balance of the information transferred along the two arms of the cardiovascular loop during HUT, with larger baroreflex involvement and smaller feedforward mechanical effects; and (iv) an increased importance of direct respiratory effects on SAP during HUT, and on both HP and SAP during MA. We demonstrate that a decomposition of the information contained in cardiovascular oscillations can reveal subtle changes in system dynamics and improve our understanding of the complexity changes during physiological challenges., (Copyright © 2018. Published by Elsevier Ltd.)

Published
2018
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