Разработка руководства по обучению для технического персонала: анализ задач обучения

The methodology of development and construction of the Training Manual for maintenance personnel is considered. Training Manual is the basic Manual used in the Type Rating Training courses. The use of Training Need Analysis (TNA) technique is also considered in the article.Рассмотрена методология разработки и построения руководства по обучению технического персонала основного учебного пособия, используемого в учебных курсах при переучивании инженерно-технического персонала на новый тип авиационной техники. В статье рассмотрена методика анализа потребности обучения, используемая при разработке данного руководства

Federal Clinical Guidelines on Rendering Help to Children with Hemolytic Uremic Syndrome

The hemolytic uremic syndrome (HUS) is a serious therapeutic problem in pediatrics and pediatric nephrology. HUS is one of the leading causes of acute renal failure with the potential of transforming into terminal chronic renal failure at various periods from the disease onset. The typical form of HUS with a diarrheal prodrome associated with Shiga toxin (STEC) is the most common form. Despite this fact, it requires careful confirmation of infectious etiology to exclude atypical HUS and HUS associated with pneumococcal infection in time. In respect of STEC-HUS it is recommended to conduct adequate symptomatic therapy with a timely dialysis connection if needed. The prognosis here will depend on the anuretic period duration and on the related central nervous system injuries. Atypical HUS is often based on genetic mutations leading to the complement cascade disfunction with uncontrolled activation of the alternative pathway. The overall prognosis for this prone to recurrence form is unfavourable, however, it is recommended to conduct aeculizumabum treatment which will block the terminal components of the complement cascade

Molecular genetic features of the development of restrictive cardiomyopathy in Russian children

Aim. To identify the proportion of restrictive cardiomyopathy (RCM), as well as cardiomyopathy (CMP) with a restrictive type of hemodynamics among all cases of genetic CMP and to determine the relative frequencies and spectrum of nucleotide variants in Russian children with RCM, as well as to search for phenogenotypic correlations.Material and methods. The study included 689 children with CMPs. All children underwent a molecular genetic testing of the target regions of 419 genes responsible for various cardiomyopathies and channelopathies using the method of massively parallel sequencing (MPS).Results. In 668 (97,0%) children, pathogenic, likely pathogenic nucleotide variants, as well as nucleotide variants with unknown clinical significance, were identified. Of these, 45 (6,7%) patients were selected to determine the molecular genetic characteristics of RCM, 20 of whom had clinical symptoms and morphofunctional structure of RCMP (3,0%), while the remaining 25 (3,7%) children were diagnosed with another CMP type with a restrictive type of hemodynamics. In total, these patients had 41 nucleotide variants in 15 different genes, while 19 (46,3%) variants were pathogenic, 12 (29,3%) — likely pathogenic, 10 (24,4%) — uncertain clinical significance. Pathogenic and likely pathogenic variants were identified in a total of 38 (84,4%) patients, while in 19 (42,2%) patients, the pathogenic variants described earlier were found. The most common genetic marker of RCM in Russian children was TNNI3 gene mutations. In total, they were identified in 12 (25%) children: with RCP — 8 (40%) patients; with CMP with a restrictive type of hemodynamics — 4 (16%) patients. At the same time, the most common mutation of the TNNI3 gene was the nucleotide variant c.575G>A, leading to the amino acid variant p.R192H, described earlier in patients with RCM and identified by us in three (15%) unrelated children with RCM. In addition, a significant difference was found between the averaged values of N-terminal pro-brain natriuretic peptide in patients with mutations in the MYH7 and TNNI3 genes (0,0039, p<0,05), as well as between the peak flow gradient values in children with mutations in TNNI3 and FLNC genes (0,0016, p<0,05), TNNI3 and MYH7 genes (0,039, p<0,05).Conclusion. The results of this study indicate a significant genetic heterogeneity of RCM in Russian children and the need for further research aimed at finding genotype-phenotype associations in order to predict the course of the disease and select the proper therapy

НОВЫЕ ВАРИАНТЫ ГЕНОМА РОССИЙСКИХ ДЕТЕЙ С ГЕНЕТИЧЕСКИ ОБУСЛОВЛЕННЫМИ КАРДИОМИОПАТИЯМИ, ВЫЯВЛЕННЫЕ МЕТОДОМ МАССОВОГО ПАРАЛЛЕЛЬНОГО СЕКВЕНИРОВАНИЯ

Background: Cardiomyopathies in children are serious, continuously progressing myocardium diseases which are characterized by a variety of the causes, symptoms, implications, and high lethality. More than 400 genes that can cause hereditary heart and vessels diseases are described in scientific literature. The application of a high-performance method of massive parallel sequencing allows to conduct the investigation of genome extended targeted areas revealing the variants and analyzing them (bioinformatics) for pathogenicity.Aims: Identification of a genetic etiology of hereditary cardiomyopathies development in children’s population of the Russian Federation.Materials and methods: The research included 103 patients with various phenotypes of cardiomyopathies aged from 3 months up to 17 years 9 months who at the moment of examination were observed in the cardiology department and the department of recovery treatment with cardiovascular diseases in the NMRCCH. All patients were performed massive parallel sequencing analyzing the targeted areas of 404 genes which mutations lead to the development of heart and vessels hereditary diseases.Results: The diagnostic algorithm based on the method of a massive parallel sequencing was developed. 176 258 minor options were identified in the explored target areas of genome of 103 patients. An average number of the revealed nucleotide replacements different from the reference sequence was 1711. We observed that about 40% of all variants founded by our means were found in MYH7, MYBPC3, TTN, MYH6, SCN5A, DSC2 and TPM1 genes. Bioinformatics analysis allowed revealing 68 novel genome variants associated with cardiomyopathy development. The reliable association of carriage of pathogenic option in MYBPC3 gene with development of hypertrophic cardiomyopathy in the Russian children was found.Conclusions: The application of the offered algorithm allowed establishing laboratory diagnoses to 99 (96.1%) patients out from 103 investigated subjects including the syndromal and non-syndromal forms of heart and vessels hereditary diseases which showed a cardiomyopathy phenotype.Обоснование. Кардиомиопатии у детей относятся к тяжелым, непрерывно прогрессирующим заболеваниям миокарда, характеризующимся разнообразием причин, симптомов и проявлений, высокой летальностью. В мировой литературе описано более 400 генов, мутации которых приводят к развитию генетически обусловленных болезней сердца и сосудов. Применение высокопроизводительного метода массового параллельного секвенирования позволяет проводить исследование протяженных таргетных областей генома для обнаружения вариантов и их дальнейшего биоинформатического анализа на предмет патогенности.Цель исследования — выявление генетической этиологии развития наследственных кардиомиопатий среди детского населения России.Методы. В исследование были включены 103 пациента с различными фенотипами кардиомиопатий в возрасте от 3 мес до 17 лет 9 мес на момент обследования, наблюдавшиеся в кардиологическом отделении и отделении восстановительного лечения детей с болезнями сердечно-сосудистой системы ФГАУ «НМИЦ здоровья детей». Всем пациентам методом массового параллельного секвенирования проведен анализ таргетных областей 404 генов, мутации в которых приводят к развитию наследственных болезней сердца и сосудов.Результаты. Разработан диагностический алгоритм на основе метода массового параллельного секвенирования. Идентифицировано 176 258 минорных вариантов у 103 пациентов в исследуемых целевых регионах генома. В среднем у каждого пациента выявлено 1711 нуклеотидных замен, отличающихся от референсной последовательности. Установлено, что около 40% обнаруженных нами вариантов приходится на гены MYH7, MYBPC3, TTN, MYH6, SCN5A, DSC2 и TPM1. Биоинформатический анализ позволил выявить 68 новых вариантов генома, ассоциированных с развитием кардиомиопатий. Обнаружена достоверная ассоциация носительства патогенного варианта гена MYBPC3 с развитием гипертрофической кардиомиопатии у российских детей — OR 3,17 (1,36–11,72; p=0,009).Заключение. Применение предложенного алгоритма позволило установить лабораторные диагнозы 99 (96,1%) пациентам из 103 обследованных, в том числе с синдромальными и несиндромальными формами наследственных болезней сердца и сосудов, проявляющимися фенотипом кардиомиопатии

Experience of the successful treatment with canakinumab of a patient with NLPC4-associated autoinflammatory syndrome with enterocolitis

The article shows the observation of rare NLPC4-associated autoinflammatory syndrome with enterocolitis and familial cold urticaria. Diagnosis is confirmed molecularly-genetically: previously not described mutation c.928C>T in the heterozygous state in NLRC4 gene is discovered by a method of the new generation sequencing. The use of a monoclonal antibody to the interleukin 1 canakinumab provided complete relief of fever and skin and intestinal symptoms in just 1 week of treatment. Later the signs of inflammation have disappeared completely; the patient’s quality of life improved and life-threatening complications were prevented. The above example demonstrates the high clinical efficacy of canakinumab in the patient with NLRC4-associated autoinflammatory syndrome and suggests promising therapeutic use of interleukin 1 blockers in such patients. There were no adverse events during canakinumab therapy

High Efficiency of Kanakinumabum for a Patient with a Late Diagnosed Chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA)

The article presents the monitoring of a severe course of CINCA/NOMID syndrome diagnosed at late stages. The use of monoclonal antibodies to IL 1 — kanakinumabum — in a patient with chronic neurological cutaneous and articular syndrome was successful: fever, cutaneous and pain syndromes were completely stopped, joint contractures decreased after one week of therapy. Laboratory parameters of the child’s disease activity (ESR and CRP) became normal after 8 weeks of treatment. Movements in the affected joints recovered completely after 24 weeks; the audiologist noted an improvement in hearing. The above clinical example demonstrates the high efficiency of kanakinumabum for a patient with chronic neurological cutaneous and articular syndrome, and shows the perspective of therapeutic application of IL 1 blocker for patients with CINCA syndrome including advanced stages of the disease. No adverse effects were noted during kanakinumabum therapy

Федеральные клинические рекомендации по оказанию помощи детям с гемолитико-уремическим синдромом

The hemolytic uremic syndrome (HUS) is a serious therapeutic problem in pediatrics and pediatric nephrology. HUS is one of the leading causes of acute renal failure with the potential of transforming into terminal chronic renal failure at various periods from the disease onset. The typical form of HUS with a diarrheal prodrome associated with Shiga toxin (STEC) is the most common form. Despite this fact, it requires careful confirmation of infectious etiology to exclude atypical HUS and HUS associated with pneumococcal infection in time. In respect of STEC-HUS it is recommended to conduct adequate symptomatic therapy with a timely dialysis connection if needed. The prognosis here will depend on the anuretic period duration and on the related central nervous system injuries. Atypical HUS is often based on genetic mutations leading to the complement cascade disfunction with uncontrolled activation of the alternative pathway. The overall prognosis for this prone to recurrence form is unfavourable, however, it is recommended to conduct aeculizumabum treatment which will block the terminal components of the complement cascade.Гемолитико-уремический синдром (ГУС) представляет собой серьезную терапевтическую проблему в педиатрии и детской нефрологии, являясь одной из ведущих причин острой почечной недостаточности с потенциальной трансформацией в терминальную хроническую почечную недостаточность в различные сроки от начала заболевания. Несмотря на то, что наиболее распространена типичная форма ГУС с диарейной продромой, ассоциированная с токсином Шига (STEC), требуется тщательное подтверждение инфекционной этиологии, чтобы вовремя исключить атипичный ГУС и ГУС, связанный с пневмококковой инфекцией. В отношении STEC-ГУС рекомендуется адекватная симптоматическая терапия со своевременным подключением диализа при необходимости. Прогноз при этом будет зависеть от продолжительности анурического периода и сопутствующих повреждений центральной нервной системы. Атипичный ГУС чаще всего имеет в основе генные мутации, приводящие к дисфункции каскада комплемента с неконтролируемой активацией альтернативного пути. При общем неблагоприятном прогнозе этой склонной к рецидивированию формы перспективным является лечение экулизумабом, блокирующим терминальные компоненты каскада комплемента

Семейный случай недостаточности декарбоксилазы L-ароматических аминокислот

Aromatic L‑amino acid decarboxylase (AADC) deficiency is rare autosomal recessive neurometabolic disorder. It caused by generalized combined deficiency of serotonin, dopamine, norepinephrine and adrenaline. This disorder is characterized by muscular hypotonia, motor development delay, oculogyric crises and impairment of the autonomic nervous system.Laboratory diagnostic of AADC deficiency in Russian Federation includes determination of the concentration of 3‑O‑methyldophamine in dried blood spots by tandem mass spectrometry and molecular analysis of the DDC gene by Sanger sequencing or next generation sequencing.Therapy of AADC deficiency includes combination of drugs which increase the formation of dopamine, inhibit its reuptake and increase the residual activity of the enzyme. The first‑line drugs are selective dopamine agonists, monoamine oxidase inhibitors of type B and vitamin B6 supplements.We present the case of management and treatment of patients with AADC deficiency. The patient’s condition was improved by using of combination therapy with pyridoxal‑5‑phosphate, pramipexole and selegiline. Significant positive dynamics was achieved on pyridoxal‑5‑phosphate therapy for the first time.Дефицит декарбоксилазы ароматических L‑аминокислот (aromatic L‑amino acid decarboxylase, AADC) – редкое аутосомно‑рецессивное нейрометаболическое заболевание, обусловленное генерализованным комбинированным дефицитом серотонина, дофамина, норадреналина и адреналина. Заболевание характеризуется мышечной гипотонией, задержкой моторного развития, окулогирными кризами, расстройствами вегетативной нервной системы. Лабораторная диагностика дефицита AADC в России основана на определении концентрации 3‑О‑метилдофамина в сухих пятнах крови методом тандемной масс‑спектрометрии, а также поиске патогенных вариантов в гене DDC методом секвенирования по Сэнгеру либо высокопроизводительного секвенирования.Терапия дефицита AADC включает комбинацию препаратов, улучшающих образование дофамина, тормозящих его обратный захват и увеличивающих остаточную активность фермента. Препаратами 1‑й линии являются селективные агонисты дофамина, ингибиторы моноаминоксидазы типа В и препараты витамина В6.Представлен собственный клинический опыт наблюдения и лечения пациентов с недостаточностью AADC. На фоне комбинированной терапии пиридоксаль‑5‑фосфатом, прамипексолом и селегилином наблюдалось улучшение состояния пациента. Впервые была достигнута выраженная положительная динамика на фоне терапии пиридоксаль‑5‑фосфатом