Algorithm for predicting sepsis in newborns with respiratory pathology and perinatal lesions of the central nervous system on mechanical ventilation

Abstract

BACKGROUND: Predicting sepsis in ventilated neonates remains a challenge in neonatology.

AIM: To increase the efficiency of predicting sepsis diagnosis in newborns by developing a decision rule for its development based on decision trees.

MATERIALS AND METHODS: This clinical study retrospectively reviewed 200 full-term newborns with respiratory pathology that are admitted to the intensive care unit and are on mechanical ventilation without clinical signs of bacterial infection.

Upon admission to the department on days 1, 3–5, and 20, an enzyme-linked immunosorbent assay determined the plasma concentration of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, granulocyte colony-stimulating factor, soluble Fas ligand, fibroblast growth factors, and nitric oxide (NO), and immunophenotyping method determined CD3⁺CD19^–, CD3^–CD19⁺, CD3⁺CD4⁺, CD3⁺CD8⁺, CD69⁺, CD71⁺, CD95⁺, HLA^–DR⁺, CD34⁺, CD14⁺, CD3^–CD56⁺; lymphocytes expressing AnnexinV-FITC⁺PI^–, and AnnexinV-FITC⁺PI⁺. The possibility of diagnosing sepsis upon intensive care unit admission was assessed by statistical cluster analysis of the total studied immunological criteria. The method of decision trees in the statistical environment R formed a diagnostic rule for predicting sepsis.

RESULTS: Visualization of the cluster analysis results of admitted patients did not exclude the presence of two clusters among them (with and without sepsis, which explain the 60.81% of the point variability).

Sepsis prediction rule are as follows: disease progression occurs if on day 1 CD95 is ≥16.8% and NO is ≤9.6 mkmol/l or CD95 is ≤16.8%, CD34 is ≤0.2%, CD69 is ≥4.12% or CD95 is ≤16.8%, CD34 is ≤0.2%, CD69 is ≤4.12%, and lymphocytes expressing AnnexinV-FITC+PI– is ≥12.3%. The diagnostic accuracy was 96.00%; sensitivity was 97.00%; specificity was 94.90%; the false-positive proportion of diagnoses was 5.10%; the false-negative proportion of diagnoses was 2.94%; the positive result accuracy was 95.19%; and the negative result was 96.88%. The disease was complicated by bacterial sepsis development on 4–5 days of observation in 45 newborns.

CONCLUSIONS: Significant importance in sepsis development belongs to the prevalence of altered immunocompetent cells over proliferation and endogenous synthesis of nitric oxide. The cumulative determination of CD95⁺, CD69⁺, AnnexinV-FITC⁺PI^–, CD34⁺, and plasma nitric oxide concentration helped diagnose sepsis development at the preclinical stage. The obtained results indirectly confirm the relevance of studies on sepsis prevention and treatment by drug correction of apoptosis and inhaled NO.

Keywords

newborn / sepsis / diagnosis / apoptosis / nitrogen oxide

References

[1] Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–1655. DOI: 10.1378/chest.101.6.1644

[2] Bone R.C., Balk R.A., Cerra F.B., et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine // Chest. 1992. Vol. 101. No. 6. P. 1644–1655. DOI: 10.1378/chest.101.6.1644 3

[3] Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6(1):2–8. DOI: 10.1097/01.PCC.0000149131.72248.E6

[4] Goldstein B., Giroir B., Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics // Pediatr Crit Care Med. 2005. Vol. 6, No. 1. P. 2–8. DOI: 10.1097/01.PCC.0000149131.72248.E6

[5] Bagnenko SF, Bajbarina EN, Beloborodov VB, et al. Sepsis: klassifikatsiya, kliniko-diagnosticheskaya kontseptsiya i lechenie. Аkad. RAN B.R. Gel’fanda, ed. 4-e izd., dop. i pererab. Moscow: Meditsinskoe informatsionnoe agentstvo; 2017. 408 p. (In Russ.)

[6] Багненко С.Ф., Байбарина Е.Н., Белобородов В.Б., и др. Сепсис: классификация, клинико-диагностическая концепция и лечение / под ред. акад. РАН Б.Р. Гельфанда. 4-е изд., доп. и перераб. Москва: Медицинское информационное агентство, 2017. 408 с.

[7] Schlapbach LJ, Straney L, Bellomo R, et al. Prognostic accuracy of age-adapted SOFA, SIRS, PELOD-2, and qSOFA for in-hospital mortality among children with suspected infection admitted to the intensive care unit. Int Care Med. 2018;44(2):179–188. DOI: 10.1007/s00134-017-5021-8

[8] Schlapbach L.J., Straney L., Bellomo R., et al. Prognostic accuracy of age-adapted SOFA, SIRS, PELOD-2, and qSOFA for inhospital mortality among children with suspected infection admitted to the intensive care unit // Int Care Med. 2018. Vol. 44, No. 2. P. 179–188. DOI: 10.1007/s00134-017-5021-8

[9] De Souza DC, Machado FR. Epidemiology of Pediatric Septic Shock. J Pediatr Intensive Care. 2019;8(1):3–10. DOI: 10.1055/s-0038-1676634

[10] De Souza D.C., Machado F.R. Epidemiology of Pediatric Septic Shock // J Pediatr Intensive Care. 2019. Vol. 8, No. 1. P. 3–10. DOI: 10.1055/s-0038-1676634

[11] Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet. 2020;395(10219):200–211. DOI: 10.1016/S0140-6736(19)32989-7

[12] Rudd K.E., Johnson S.C., Agesa K.M., et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study // Lancet. 2020. Vol. 395, No. 10219. P. 200–211. DOI: 10.1016/S0140-6736(19)32989-7

[13] Weiss SL, Peters MJ, Alhazzani W, et al. Surviving Sepsis Campaign International Guidelines for the Management Sepsis and Septic Shock and Sepsis-associated Organ Dysfunction in Children. Pediatr Crit Care Med. 2020;21(2):e52–e106. DOI: 10.1097/PCC.0000000000002198

[14] Weiss S.L., Peters M.J., Alhazzani W., et al. Surviving Sepsis Campaign International Guidelines for the Management Sepsis and Septic Shock and Sepsis-associated Organ Dysfunction in Children // Pediatr Crit Care Med. 2020. Vol. 21, No. 2. P. e52–e106. DOI: 10.1097/PCC.0000000000002198

[15] Lekmanov AU, Mironov PI, Aleksandrovich YuS, et al. Sepsis in children: federal clinical guideline (draft). Russian Journal of Pediatric Surgery, Anesthesia and Intensive Care. 2021;11(2):241–292. (In Russ.) DOI: 10.17816/psaic969

[16] Лекманов А.У., Миронов П.И., Александрович Ю.С., и др. Сепсис у детей: федеральные клинические рекомендации (проект) // Российский вестник детской хирургии, анестезиологии и реаниматологии. 2021. Т. 11, № 2. С. 241–292. DOI: 10.17816/psaic969

[17] Evans IVR, Phillips GS, Alpern ER, et al. Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis. JAMA. 2018;320(4):358–367. DOI: 10.1001/jama.2018.9071

[18] Evans I.V.R., Phillips G.S., Alpern E.R., et al. Association between the New York sepsis care mandate and in-hospital mortality for pediatric sepsis // JAMA. 2018. Vol. 320, No. 4. P. 358–367. DOI: 10.1001/ jama.2018.9071

[19] Tidswell R, Inada-Kim M, Singer M. Sepsis: the importance of an accurate final diagnosis. Lancet Respir Med. 2021;9(1):17–18. DOI: 10.1016/S2213-2600(20)30520-8

[20] Tidswell R., Inada-Kim M., Singer M. Sepsis: the importance of an accurate final diagnosis // Lancet Respir Med. 2021. Vol. 9, No. 1. P. 17–18. DOI: 10.1016/S2213-2600(20)30520-8

[21] Martischang R, Pires D, Masson-Roy S, et al. Promoting and sustaining a historical and global effort to prevent sepsis: the 2018 World Health Organization SAVE LIVES, Clean Your Hands campaign. Crit Care. 2018;22(1):92. DOI: 10.1186/s13054-018-2011-3

[22] Martischang R., Pires D., Masson-Roy S., et al. Promoting and sustaining a historical and global effort to prevent sepsis: the 2018 World Health Organization SAVE LIVES, Clean Your Hands campaign // Crit Care. 2018. Vol. 22, No. 1. P. 92. DOI: 10.1186/s13054-018-2011-3

[23] Wong HR, Weiss SL, Giuliano JS Jr, et al. Testing the Prognostic Accuracy of the Updated Pediatric Sepsis Biomarker Risk Model. PLoS ONE. 2016;9(1):e86242. DOI: 10.1371/journal.pone.0086242

[24] Wong H.R., Weiss S.L., Giuliano J.S. Jr, et al. Testing the Prognostic Accuracy of the Updated Pediatric Sepsis Biomarker Risk Model // PLoS ONE. 2016. Vol. 9, No. 1. P. e86242. DOI: 10.1371/journal.pone.0086242

[25] Wong HR, Caldwell JT, Cvijanovich NZ, et al. Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model. Sci Transl Med. 2019;11(518):eaax9000. DOI: 10.1126/scitranslmed.aax9000

[26] Wong H.R., Caldwell J.T., Cvijanovich N.Z., et al. Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model // Sci Transl Med. 2019. Vol. 11, No. 518. P. eaax9000. DOI: 10.1126/scitranslmed.aax9000

[27] Gorgis N, Asselin JM, Fontana C, et al. Evaluation of the association of early elevated lactate with outcomes in children with severe sepsis or septic shock. Pediatr Emerg Care. 2019;35(10):661– 665. DOI: 10.1097/PEC.0000000000001021

[28] Gorgis N., Asselin J.M., Fontana C., et al. Evaluation of the association of early elevated lactate with outcomes in children with severe sepsis or septic shock // Pediatr Emerg Care. 2019. Vol. 35, No. 10. P. 661–665. DOI: 10.1097/PEC.0000000000001021

[29] Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–810. DOI: 10.1001/jama.2016.0287

[30] Singer M., Deutschman C.S., Seymour C.W., et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3) // JAMA. 2016. Vol. 315, No. 8. P. 801–810. DOI: 10.1001/jama.2016.0287

[31] Matics TJ, Sanchez-Pinto LN. Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the Sepsis-3 definitions in critically ill children. JAMA Pediatr. 2017;171(10):e172352. DOI: 10.1001/jamapediatrics.2017.2352

[32] Matics T.J., Sanchez-Pinto L.N. Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the Sepsis-3 definitions in critically ill children // JAMA Pediatr. 2017. Vol. 171, No. 10. e172352. DOI: 10.1001/jamapediatrics.2017.2352

[33] Boeddha N, Schlapbach N, Driessen G, et al. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS). Crit Care. 2018;22(1):143. DOI: 10.1186/s13054-018-2052-7

[34] Boeddha N., Schlapbach N., Driessen G., et al. Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS) // Crit Care. 2018. Vol. 22, No. 1. P. 143. DOI: 10.1186/s13054-018- 2052-7

[35] Hagedoorn NN, Borensztajn D, Nijman RG, et al. Development and validation of a prediction model for invasive bacterial infections in febrile children at European Emergency Departments: MOFICHE, a prospective observational study. Arch Dis Child. 2021;106(7):641–647. DOI: 10.1136/archdischild-2020-319794

[36] Hagedoorn N.N., Borensztajn D., Nijman R.G., et al. Development and validation of a prediction model for invasive bacterial infections in febrile children at European Emergency Departments: MOFICHE, a prospective observational study // Arch Dis Child. 2021. Vol. 106, No. 7. P. 641–647. DOI: 10.1136/archdischild-2020-319794

[37] Khemani RG, Smith L, Lopez-Fernandez YM, et al. Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): an international, observational study. Lancet Respir Med. 2019;7(2):115–128. DOI: 10.1016/S2213-2600(18)30344-8

[38] Khemani R.G., Smith L., Lopez-Fernandez Y.M., et al. Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): an international, observational study // Lancet Respir Med. 2019. Vol. 7, No. 2. P. 115–128. DOI: 10.1016/S2213-2600(18)30344-8

[39] Fleischmann C, Goldfarb DM, Schlattmann P, et al. The global burden of paediatric and neonatal sepsis: a systematic review. The Lancet Respiratory medicine. 2018;6(3):223–230. DOI: 10.1016/ S2213-2600(18)30063-8

[40] Fleischmann C., Goldfarb D.M., Schlattmann P., et al. The global burden of paediatric and neonatal sepsis: a systematic review // The Lancet Respiratory medicine. 2018. Vol. 6, No. 3. P. 223–230. DOI: 10.1016/S2213-2600(18)30063-8

[41] Lekmanov AU, Mironov PI. Pediatric sepsis — time to reach agreement. Russian Bulletin of Perinatology and Pediatrics. 2020;65(3):131–137. (In Russ.) DOI: 10.21508/1027-4065-2020-65-3-131-137

[42] Лекманов А.У., Миронов П.И. Сепсис в педиатрической практике — пора договариваться // Российский вестник перинатологии и педиатрии. 2020. Т. 65, № 3. С. 131–137. DOI: 10.21508/1027-4065-2020-65-3-131-137

[43] Lamping F, Jack T, Rubsamen N, et al. Development and validation of a diagnostic model for early differentiation of sepsis and non-infectious SIRS in critically ill children — a data-driven approach using machine learning algorithms. BMC Pediatr. 2018;18(1):112. DOI: 10.1186/s12887-018-1082-2

[44] Lamping F., Jack T., Rubsamen N., et al. Development and validation of a diagnostic model for early differentiation of sepsis and non-infectious SIRS in critically ill children — a data-driven approach using machine learning algorithms // BMC Pediatr. 2018. Vol. 18, No. 1. P. 112. DOI: 10.1186/s12887-018-1082-2

[45] Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ. 2016;353:i1585. DOI: 10.1136/bmj.i1585

[46] Gotts J.E., Matthay M.A. Sepsis: pathophysiology and clinical management // BMJ 2016. Vol. 353. P. i1585. DOI: 10.1136/bmj.i1585

[47] Bankalari E. Lungs newborns. Problems and contradictions in neonatology. Polin N, editor. Moscow: Logosfera; 2015. P. 342–354.

[48] Банкалари Э. Легкие новорожденных / под ред. Р. Полина; пер. с англ.; под ред. Д.Ю. Овсянникова. Москва: Логосфера, 2015. С. 342–354.

[49] 38th International Symposium on Intensive Care and Emergency Medicine. Crit Care. 2018;22(Supple 1):Р018. DOI: 10.1186/s13054-018-1973-5

[50] 38th International Symposium on Intensive Care and Emergency Medicine // Critical Care. 2018. Vol. 22, Suppl 1. Р. Р018. DOI: 10.1186/s13054-018-1973-5

[51] Abdullayev E, Kilic O, Bozan G, et al. Clinical, laboratory features and prognosis of children receiving IgM-enriched immunoglobulin (3 days vs. 5 days) as adjuvant treatment for serious infectious disease in pediatric intensive care unit: a retrospective single-center experience (PIGMENT study). Human Vaccines & Immunotherapeutics. 2020;16(8):1997–2002. DOI: 10.1080/21645515.2019.1711298

[52] Abdullayev E., KiLic O., Bozan G., et al. Clinical, laboratory features and prognosis of children receiving IgM-enriched immunoglobulin (3 days vs. 5 days) as adjuvant treatment for serious infectious disease in pediatric intensive care unit: a retrospective single-center experience (PIGMENT study) // Human Vaccines & Immunotherapeutics. 2020. Vol. 16, No. 8. P. 1997–2002. DOI: 10.1080/21645515.2019.1711298

[53] Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13(3):260–268. DOI: 10.1016/S1473-3099(13)70001

[54] Hotchkiss R.S., Monneret G., Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach // Lancet Infect Dis. 2013. Vol. 13, No. 3. P. 260–268. DOI: 10.1016/S1473-3099(13)70001

[55] Fung JST, Akech S, Kissoon N, et al. Determining predictors of sepsis at triage among children under 5 years of age in resourcelimited settings: A modified Delphi process. PLoS One. 2019;14(1):e0211274. DOI: 10.1371/journal.pone.0211274

[56] Fung J.S.T., Akech S., Kissoon N., et al. Determining predictors of sepsis at triage among children under 5 years of age in resourcelimited settings: A modified Delphi process // PLoS One. 2019. Vol. 14, No. 1. P. e0211274. DOI: 10.1371/journal.pone.0211274

[57] Pukhtinskaya MG, Estrin VV. Strategy for the prevention of bacterial complications with inhaled nitrogen oxide in newborns. Russian Journal of Pediatric Surgery, Anesthesia and Intensive Care. 2021;11(2):141–150. DOI: 10.17816/psaic960

[58] Пухтинская М.Г., Эстрин В.В. Стратегия профилактики бактериальных осложнений ингаляционным оксидом азота у новорожденных // Российский вестник детской хирургии, анестезиологии и реаниматологии. 2021. Т. 11, № 2. С. 141–150. DOI: 10.17816/psaic960

[59] Youn YА. The role of cytokines in seizures: interleukin (IL)-1β, IL-1Ra, IL-8, and IL-10. Korean J Pediatr. 2013; 56(7):271–274. DOI: 10.3345/kjp.2013.56.7.271

[60] Youn Y.А. The role of cytokines in seizures: interleukin (IL)-1β, IL-1Ra, IL-8, and IL-10 // Korean J Pediatr. 2013. Vol. 56, No. 7. P. 271–274. DOI: 10.3345/kjp.2013.56.7.271

[61] Petel D, Winters N, Gore GC, et al. Use of C-reactive protein to tailor antibiotic use: a systematic review and meta-analysis. BMJ Open. 2018;8(12):e022133. DOI: 10.1136/bmjopen-2018-022133

[62] Petel D., Winters N., Gore G.C., et al. Use of C-reactive protein to tailor antibiotic use: a systematic review and metaanalysis // BMJ Open. 2018. Vol. 8, No. 12. P. e022133. DOI: 10.1136/bmjopen-2018-022133

[63] Popov D, Yaroustovsky M, Lobacheva G. Prevention of infectious complications after heart surgery in children: procalcitonin-guided strategy. Kardiochir Torakochirurgia Pol. 2014;11(2):140–144. DOI: 10.5114/kitp.2014.43840

[64] Popov D., Yaroustovsky M., Lobacheva G. Prevention of infectious complications after heart surgery in children: procalcitoninguided strategy // Kardiochir Torakochirurgia Pol. 2014. Vol. 11, No. 2. P. 140–144. DOI: 10.5114/kitp.2014.43840

[65] Shapiro NI, Trzeciak S, Hollander JE, et al. A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis. Critical Care Mediсine. 2009;37(1):96–104. DOI: 10.1097/CCM.0b013e318192fd9d

[66] Shapiro N.I., Trzeciak S., Hollander J.E., et al. A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis // Critical Care Mediсine. 2009. Vol. 37, No. 1. Р. 96–104. DOI: 10.1097/CCM.0b013e318192fd9d

[67] Gibot S, Béné MC, Noel R, et al. Combination biomarkers to diagnose sepsis in the critically ill patient. American Journal of Respiratory and Critical Care Medicine. 2012;186(1):65–71. DOI: 10.1164/rccm.201201-0037OC

[68] Gibot S., Béné M.C., Noel R., et al. Combination biomarkers to diagnose sepsis in the critically ill patient // American Journal of Respiratory and Critical Care Medicine. 2012. Vol. 186, No. 1. Р. 65–71. DOI: 10.1164/rccm.201201-0037OC

[69] Helliksson F, Wernerman J, Wiklund L, et al. The combined use of three widely available biochemical markers as predictor of organ failure in critically ill patients. Scandinavian Journal of Clinical and Laboratory Investigation. 2016;76(6):479–485. DOI: 10.1080/00365513.2016.1201850

[70] Helliksson F., Wernerman J., Wiklund L., et al. The combined use of three widely available biochemical markers as predictor of organ failure in critically ill patients // Scandinavian Journal of Clinical and Laboratory Investigation. 2016. Vol. 76, No. 6. Р. 479–485. DOI: 10.1080/00365513.2016.1201850

[71] Mayeux R. Biomarkers: potential uses and limitations. NeuroRx. 2004;1(2):182–188. DOI: 10.1602/neurorx.1.2.182

[72] Mayeux R. Biomarkers: potential uses and limitations // NeuroRx. 2004. Vol. 1, No. 2. Р. 182–188. DOI: 10.1602/neurorx.1.2.182

[73] Radivilko AS, Grigoryev EV, Shukevich DL, et al. Multiple organ failure: early diagnosis and prediction. Russian Journal of Anaesthesiology and Reanimatology. 2018;(6):15–21. DOI: 1.17116/anesthesiology201806115

[74] Радивилко А.С., Григорьев Е.В., Шукевич Д.Л., Плотников Г.П. Прогнозирование и ранняя диагностика полиорганной недостаточности // Анестезиология и реаниматология. 2018. № 6. С. 15–21. DOI: 10.17116/anesthesiology201806115

[75] Collins GS, Reitsma J, Altman DG, et al. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. BMJ. 2015;350:g7594. DOI: 10.1136/bmj.g7594

[76] Collins G.S., Reitsma J.B., Altman D.G., et al. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement // BMJ. 2015. Vol. 350. P. g7594. DOI: 10.1136/bmj.g7594

[77] Kondrashova NV, Tomilin VV. Solving the problem of diagnosing diseases with a mild form of coagulopathy and thrombocytopathy based on methods of expert assessments. System Technologies. Interuniversity collection of scientific works. 2010;(6):104–114. (In Russ.)

[78] Кондрашова Н.В., Томилин В.В. Решение задачи диагностики заболеваний легкой формой коагулопатии и тромбоцитопатии на основе методов экспертных оценок // Системные технологии. Межвузовский сборник научных работ. 2010. № 6. С. 104–114.

[79] Zhuravlev JuI, Rjazanov VV, Sen’ko OV. «Raspoznavanie». Matematicheskie metody. Programmnaya sistema. Prakticheskie primeneniya Moscow: Fazis; 2006. 176 p. (In Russ.)

[80] Журавлев Ю.И., Рязанов В.В., Сенько О.В. «Распознавание». Математические методы. Программная система. Практические применения. Москва: Фазис, 2006. 176 c.

[81] Orlov AI. Current status of nonparametric statistics. Polythematic network electronic scientific journal of the Kuban State Agrarian University. 2015;(106):239–269. (In Russ.)

[82] Орлов А.И. Современное состояние непараметрической статистики // Политематический сетевой электронный научный журнал Кубанского государственного аграрного университета. 2015. № 106. С. 239–269.

[83] Pukhtinskaya MG, Estrin VV, Gulova ES. Clinical and diagnostic significance of apoptosis in the pathogenesis of neutropenia and bacterial complications in newborns with respiratory distress syndrome. Cytokines and inflammation. 2011;10(2):66–69 (In Russ.)

[84] Пухтинская М.Г., Эстрин В.В., Гулова Е.С. Клинико-диагностическое значение апоптоза в патогенезе нейтропении и бактериальных осложнений у новорожденных с респираторным дистресс-синдромом // Цитокины и воспаление. 2011. Т. 10, № 2. С. 66–69.

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Pukhtinskaya M.G., Estrin V.V.