Almazov National Medical Research Centre Research Articles

Vitamin D Metabolism Parameters and Cytokine Profile in COVID-19 Patients with Bolus Cholecalciferol Supplementation.

This study represents the next stage of the open-label randomized pilot conducted by the Almazov National Medical Research Centre. A total of 44 hospitalized patients, comparable in demographic, clinical, laboratory and instrumental baseline characteristics, with moderate/severe COVID-19 were included. All patients had similar doses of concomitant corticosteroid therapy. Twenty-two patients received 50,000 IU cholecalciferol on the first and eighth days of hospitalization. The serum 25(OH)D, 1,25(OH)2D and 28 plasma cytokines were estimated for each group initially and on the ninth day of hospitalization. Initially, there were no differences in the 1,25(OH)2D and cytokine levels in patients with vitamin D deficiency and normal 25(OH)D. Bolus cholecalciferol therapy at a total dose of 100,000 IU led to an increase in 25(OH)D levels in hospitalized patients with COVID-19, while the levels of the active metabolite (1,25(OH)2D) did not show significant differences between the groups or in its increased level over time, regardless of cholecalciferol supplementation. Furthermore, cholecalciferol supplementation at a total dose of 100,000 IU did not affect the majority of the cytokines estimated on the ninth day of hospitalization, except for the pro-inflammatory marker IL-1b, the concentration of which was lower in the group of patients without vitamin D supplementation. The 25(OH)D level was positively associated with an anti-inflammatory immune response, but cholecalciferol supplementation at a total dose of 100,000 IU did not affect the active-form vitamin D or cytokine expression levels. This fact may be explained by the impact of corticosteroid therapy, and it requires further investigation in a post-COVID-19 context.

КЛИНИЧЕСКОЕ ЗНАЧЕНИЕ РЕАКТИВАЦИИ ГЕРПЕСВИРУСНЫХ ИНФЕКЦИЙ У ДЕТЕЙ С ОНКОЛОГИЧЕСКИМИ ЗАБОЛЕВАНИЯМИ

Herpesvirus infection (HVI) reactivation in children with cancer is a common complication during the period of postcytostatic immunosuppression and occurs mostly after courses of high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (HSCT). Clinical manifestations can range from asymptomatic viral reactivation and chemo-induced cytopenia worsening to fatal outcomes of the disease coupled with multiorgan involvement. The purpose of the research was to analyze cases of HVI reactivation in oncological pediatric patients in order to identify the risk factors for HVI development, features of its clinical manifestations and the effectiveness of antiviral therapy. Materials and methods used: a single-center retrospective cohort study was provided. The register of HVI reactivation cases in patients receiving antitumor therapy at the V.A. Almazov National Medical Research Centre of the Ministry of Healthcare of Russia (Saint Petersburg, Russia) in Jan. 2017-Jul. 2021 was analyzed. Routine monitoring of HVI reactivation (CMV, HHV-6A/B, EBV) included determination of viral DNA in patients’ biological materials by PCR using the AmpliSens test system on a Rotor-Gene device (amplifier). Results: 40 cases of HVI reactivation were registered, 22 (55%) were associated with cytomegalovirus infection (CMV), 4 (10%) with human herpes virus 6 (HHV-6A/B), 3 (7.5%) with Epstein-Barr virus (EBV) and 11 (27.5%) mixed. DNAemia was registered in 55%, organ damage in 45%. More often, reactivation of HVI developed after allogeneic HSCT (alloHSCT) (42,5%), autologous HSCT (autoHSCT) (40%). A statistically significant decrease of HVI reactivation cases was observed in patients after alloHSCT without TCRaβ depletion (53% v. 5,5%, p=0.036). Antiviral therapy was carried out in all patients. The first-line drug most often was ganciclovir (60%). Second line antiviral therapy was required in 10% of cases and those were the only CMV infection cases. Conclusion: a statistically significant decrease of HVI reactivation cases was observed in patients without TCRaβ depletion in alloHSCT. The clinical signs usually are not specific and require routine laboratory monitoring. Adequate antiviral therapy allowed achieving infectious control over HVI in most of the cases.

Blinatumomab in pediatric acute lymphoblastic leukemia: one center experience

Background. Despite the successes achieved in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), overcoming the toxicity of standard chemotherapy regimens and the treatment of relapsed/refractory (r/r) forms of the disease remains relevant. The most promising option is to use immunotherapy (IT), including a monoclonal antibody blinatumomab (BM). The purpose of the study. To analyze indications of using, as well as efficacy and tolerability of BM in children with V-ALL. Materials and methods. From April 2016 to January 2024 a retrospective assessment of using of BM in children with B-ALL in the chemotherapy department of oncohematological diseases and TCM for children in Almazov National Medical Research Centre was performed. Results. The study included 53 patients, including 28 (53 %) girls and 25 (47 %) boys with median age of 7,7 (2,08–19,8) years. Indications for using of BM were as follows: (1) consolidation of remission (CR) with primary ALL (n = 17, 32 %); (2) persistence of minimal residual disease (MRD) (n = 23, 43 %) after completion of chemotherapy (CT) induction or before the stage of allogeneic haematopoietic stem cell transplantation (alloHSCT); (3) replacement of the standard CR due to the previous toxicity of СT or other contraindications to its implementation (n = 12, 23 %); (4) salvage therapy for r/r ALL (n = 1, 1,9 %). The status of MRD-negative remission after the 1st course of IT was achieved in 89 % of cases. Therapy using BM in a patient with the r/r ALL and total blast infiltration of the bone marrow was effective and facilitated reducing the tumor population to 7,2% by day 15 of therapy, however, there was a fatal outcome due to development and progression of preexisted severe infection. The most common variants of grade III–IV toxicity were leuko-/neutropenia (28 %) and neurotoxicity (3,7 %). BM dose reduction for the purpose of relieving toxicity was required in 19 % of patients, while the median days of therapy with dose reduction was 4. Corticosteroids were used for this purpose in 11 % of cases, antibacterial therapy — in 13 %. At the time of results evalution, there were no relapses of the disease in the study group. The article analyzes the international experience of using BM in patients with B-ALL.Conclusion. Our experience and the presented literature data demonstrate a reasonable expansion of indications for using of BM in children with B-ALL with high efficacy and satisfactory toxicity profile.

Robot-assisted surgery of renal cell carcinoma in comorbid and frail patients

BACKGROUND: Renal cell carcinoma is predominantly observed in elderly patients. Many of them have multiple comorbidities, which can limit the feasibility of surgical treatment. The search for an optimal approach of radical treatment for comorbid and frail patients remains a current challenge. AIM: To evaluate the perioperative outcomes of robot-assisted partial nephrectomy and radical nephrectomy in comorbid and frail patients with renal cell carcinoma. MATERIALS AND METHODS: At the Almazov National Medical Research Centre we retrospectively studied the results of 118 comorbid and frail patients who underwent robot-assisted surgeries for localized renal cell carcinoma from 2012 to 2022. Mean age of men was 65.7 ± 11.4 years, and women was 61.3 ± 13.1 years. Comorbidity was assessed using the Charlson Comorbidity Index (CCI). Frailty was determined using a modified Frailty index (mFI-11). Robot-assisted partial nephrectomy and radical nephrectomy were perfomed by single experienced robotic surgeon. Perioperative functional outcomes were assessed. Renal function was evaluated based on glomerular filtration rate (GFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula before surgery and at 1.3, and 6 months after surgery. RESULTS: Among 118 patients, 71 (60.2%) underwent robot-assisted partial nephrectomy, while 47 (39.8%) underwent radical nephrectomy. Postoperative complications occurred in 15 (12.7%) of patients for robot-assisted surgeries. There were no positive surgical margins. Mortality in the early postoperative period amounted to 1.7% and was associated with the development of acute cardiovascular failure. CONCLUSIONS: Robot-assisted partial nephrectomy and radical nephrectomy for renal cell carcinoma in comorbid and “fragile” patients — the safest and optimal method of treatment, accompanied by minimal perioperative complications and mortality.

PHYSICAL AND MECHANICAL PROPERTIES OF CONDUITS DURING THE FORMATION OF THE OUTFLOW TRACT INTO THE PULMONARY ARTERY

HighlightsWe have evaluated the rigidity and distensibility of conduits in the long-term period using transthoracic echocardiography. The assessment of elastic properties will make it possible to predict degenerative changes in the conduit and choose the optimal prosthesis. AbstractAim. To evaluate changes in the rigidity and distensibility of conduits in patients after the formation of an outflow tract into the pulmonary artery in comparison with the control group of “healthy” children.Methods. The prospective non-randomized two-center study included 58 people with right ventricular dysfunction who underwent primary conduit implantation between the ages of 3 and 15 years. To assess the elastic properties of the pulmonary artery, a control group of 25 patients (healthy children who agreed to participate in the study) was introduced. The study was carried out at the Meshalkin National Medical Research Center and the Almazov National Medical Research Centre. All patients were divided into 4 groups: healthy children (n = 25), formation of the outflow tract with a pulmonary homograft (n = 28), and formation of the outflow tract with Contegra conduit (n = 19), formation with a xenopericardial conduit (n = 11).Results. The only differences between the groups were the RV EDV index, RV CVD index, RV FIP, severe pulmonary regurgitation, and tricuspid regurgitation. There is a significant difference between the groups in the long-term period (after 12 and 24 months), both in terms of rigidity and elasticity. The only difference in the long-term period after 12 months was the degree of tricuspid regurgitation, which was significantly lower in the control group. After 24 months, the peak gradient between the right ventricle and the pulmonary artery was different, which was significantly higher in the group of xenopericardial conduits and the degree of pulmonary regurgitation, which was significantly lower in the control group.Conclusion. The conduits show higher stiffness in the long-term period in contrast to the normal pulmonary artery, which may affect the durability of the conduits.

Biomarkers and predictors of postoperative necrotizing enterocolitis in neonates with duct-dependent congenital heart defects undergoing cardiac surgery: a cohort study

The development of necrotizing enterocolitis (NEC) in neonates with duct-dependent congenital heart defects (CHD) who underwent cardiac surgery is accompanied by high mortality. Analysis of predictors is necessary for understanding the pathophysiology of NEC and development of approaches for prevention to achieve favorable outcomes of cardiac surgery. The purpose of the study was to develop a prognostic model for predicting the development of NEC after cardiac surgery in neonates with duct-dependent CHD. Methods. A prognostic cohort study was performed that included full-term neonates with duct-dependent CHD who underwent cardiac surgery at the Almazov National Medical Research Center from January 2021 to September 2023. The outcome was the development/absence of stage IB-III NEC in the postoperative period. Biomarkers of NEC (intestinal fatty acid binding protein (i-FABP, ng/ml), claudin-3 (CLDN3, ng/ml), calprotectin (CALPR, ng/ml), ischemia modified albumin (IMA, ng/ml), vascular endothelial growth factor A (VEGF A, pg/ml)) were measured by ELISA in the blood serum before cardiac surgery and 12-14 hours after surgery. We also analyzed clinical characteristics of neonates, C-reactive protein levels, complete blood count, abdominal ultrasound, ejection fraction (EF, Teicholtz) in the preoperative and postoperative periods, surgical parameters, P(v-a)CO2/C(a-v)O2 upon arrival from the operating room, vasoactive inotropic score (VIS) and arterial blood lactate levels in the first 24 hours after surgery. The association between predictors and the development of NEC after cardiac surgery was assessed using univariate and multivariate logistic regression analysis. Internal validation of the model was performed using 10-fold cross-validation. Results. During the observation period, 187 neonates underwent surgical treatment of duct-dependent CHD, of which 32 children developed stage IB-III NEC in the postoperative period (17.1%), two neonates required surgical treatment of NEC (6.3%). After meeting the non-inclusion and exclusion criteria, two groups of patients were formed: a main group (30 neonates who developed stages IB-III NEC in the postoperative period, of which stage III NEC was in one neonate) and a comparison group (40 neonates without NEC). Groups were comparable by types of CHD. Predictors associated with NEC (univariate analysis): intrauterine growth retardation (IUGR), formula feeding before surgery, high levels of IMA before on the first postoperative day (POD), procedures performed before surgery (Rashkind procedure/valvuloplasty/stenting), lower EF in in the early postoperative period, a higher maximum level of VIS in the first 24 hours after surgery, as well as a higher level of IR in the superior mesenteric artery (SMA) and thickening of the intestinal wall on the first postoperative day (POD) Independent preoperative predictors of NEC (AUC of model 0.885, specificity 0.867): IUGR (OR 32.2 (1.4-730.3), p=0.029), formula feeding (OR 12.6 (2.6-60.2), p=0.002), IMA level before surgery (OR 1.03 (1.01-1.04), p=0.004), CLDN3 level before surgery (OR 0.5 (0.3-0.9), p=0.013). Independent early postoperative predictors of NEC: IMA level on 12-14 hour after surgery (OR 1.02 (1.01-1.03), p=0.030), P(v-a)CO2/C(a-v)O2 immediately after surgery (OR 2.3 (1.2-4.4), p=0.008), IR>0.93 in SMA (OR 7.2 (1.6-32.4), p=0.011) and thickness of intestinal wall by ultrasound on POD 1 (OR 4.9 (1.3-19.2), p=0.021). Adding of VEGF A level (12-14 hour after surgery, negatively associated with NEC) to the model increased the specificity, but the predictor was not significant. AUC of postoperative model 0.862, specificity 0.800. The final model included preoperative (IUGR, formula feeding) and postoperative predictors (IMA, P(v-a)CO2/C(a-v)O2, IR of SMA>0.93, intestinal wall thickness), AUC=0.921, specificity 0.83. Conclusion. The identified predictors indirectly indicate the role of hypoxia in the pathophysiology of NEC in term neonates with duct-dependent CHD. Breast milk feeding/mixed feeding in the preoperative period may help reduce the risk of NEC in the postoperative period. Low levels of CLDN3 before surgery were associated with the development of NEC, but the interpretation of the result is controversial.

Possibilities of Predicting Peak Oxygen Consumption in Patients With Chronic Heart Failure According to the 6‑Minute Walk Test

To determine the correlation between the results of the 6-minute walk test (6MWT) and peak oxygen consumption (VO2peak) for populations of patients with chronic heart failure with pronounced clinical and demographic differences; to study a possibility of indirect measurement of VO2peak based on the results of 6MWT using the formulas available from the literature. Two databases were analyzed: 50 patients included in the AEROFIT study (group A), and 31 patients from the Almazov National Medical Research Center (group B). The inclusion criteria were the availability of data from the cardiopulmonary stress test and the 6MWT. The possibility of predicting VO2peak was calculated based on the results of 6MWT using the formulas reported in the literature (L. P. Cahalin et al., 1996; R. M. Ross et al., 2010; R. A. Adedoyin et al., 2010). The predictive accuracy of the models was assessed using the coefficient of determination (R2). The relationship between functional and clinical-demographic indicators was assessed using the Pearson or Spearman correlation analysis. The study groups differed significantly in all parameters, except for the proportion of men and the mean VO2peak. Group B patients were 20 years younger than group A patients, had a lower left ventricular ejection fraction (24.06±7.75 and 41.52±10.48 %, respectively; p<0.001), and covered a 130 m shorter distance in the 6MWT. Despite the absence of a significant difference in VO2peak between groups A and B (13.6 and 13.1 ml / kg / min, respectively; p=0.6581), 61 % of group B patients and 20% of group A belonged to Weber functional class IV. In group A, the 6MWT distance correlated closely with VO2peak (R=0.78; p<0.01) and weakly with age (R=0.4) and body mass index (R=0.3). In group B, the 6MWT distance correlated only with VO2peak (R=0.77; p<0.01). For group A, the R.M. Ross et al. model demonstrated high accuracy in determining the mean VO2peak value with a 0.06% prediction error normalized to measured VO2peak. For group B, none of the models showed satisfactory predictive accuracy. The Ross and Cahalin models showed the best coefficients of determination for groups A and B: Group A, Ross et al. (R2=0.58) and Cahalin et al. (R2=0.59); Group B, Ross et al. (R2=0.59) and Cahalin et al. (R2=0.6). In two groups of patients with a statistically insignificant difference in the mean values of VO2peak, the mean values of 6MWT distance were significantly different, although these indicators correlated closely. The VO2peak prediction models showed satisfactory accuracy for estimation of mean VO2, but poor accuracy for estimation of individual values. A better predictive accuracy is determined by similar clinical and demographic characteristics between the training and testing populations, and likely also by models based on larger, more diversified populations.

Analysis of clinical manifestations and spectrum of pharmacotherapy in Moscow and St. Petersburg cohorts of patients with adult-onset Still's disease

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease of unknown etiology characterized by clinical manifestations such as fever, non-stable maculopapular rash, arthritis and/or arthralgias and leukocytosis with neutrophilia.Objective: to analyze the spectrum of clinical manifestations of AOSD and pharmacotherapy in real clinical practice.Material and methods. A cross-sectional study included 111 patients with a confirmed diagnosis of AOSD according to the Yamaguchi criteria, who were treated in two large Russian centers from 2019 to 2022: V.A. Nasonova Research Institute of Rheumatology (Moscow) and Almazov National Medical Research Centre (Saint Petersburg).Results and discussion. We analyzed the spectrum of clinical manifestations throughout the course of the disease. The spectrum of clinical manifestations of AOSD in our study was shown to be similar to the results of other studies. It was found that the frequency of the different clinical manifestations did not differ significantly.The majority of patients (74%) in our cohort received glucocorticosteroids (GC) in combination with disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs (bDMARDs). Monotherapy with GC was used in only 9% of patients. Up to 80% of patients received methotrexate (MTX) at various stages of the disease. For the treatment of patients refractory to GC and MTX therapy, bDMARDs were prescribed (44% of cases), most frequently interleukin-6 inhibitors (34%). In the St. Petersburg cohort, 13 (31.7%) of 41 patients were taking colchicine, which enabled control of disease manifestations and a reduction in the need for GC in 9 of them.Conclusion. Thus, we can draw a preliminary conclusion about the presence of steroid dependence in patients with AOSD. Up to 79.3% of AOSD patients are forced to take GC for a long period of time, which is associated with the risk of complications. Further studies on the optimal profile of bDMARDs are needed, as well as the role of colchicine as a potential therapeutic option for certain clinical and immunological subtypes of AOSD.

Growth kinetics of benign neuroepithelial brain tumors in children with relapse

The problem of treating children with recurrent cerebral tumors cannot be solved without effective prediction of recurrent blastomatous growth. The main question will be, in addition to the possible risks of tumor recurrence, when should regrowth of the neoplasm be expected in time? In our opinion, one of the probable ways to solve this problem is to study the kinetics of tumor growth and create a mathematical model for it. The aim of the study was to analyze the kinetic features of the continued growth of benign neuroepithelial brain tumors in children after surgical treatment. The study included the results of an MRI of a 32 patients under the age of 17 years. All patients underwent brain tumor resection for the first time in the Department for Children Polenov Neurosurgical Institute (Almazov National Medical Research Centre). All patients had a relapse/continued tumor growth, as well as a benign nature of the neoplasm, which was confirmed pathomorphologically. To construct the kinetic curves, volumetric indicators of tumors obtained by virtual 3D-modeling were used. Depending on the histotype, the tumor growth rate was determined by the formula: v = (VT-VO)/T, and a graphical assessment of changes in the volume of the neoplasm was carried out – the construction of kinetic curves. Further, the most typical kinetic curves for each histological type of benign neuroepithelial tumors were identified.

Predictors of unsuccessful radiofrequency catheter ablation of idiopathic ventricular arrhythmias in children

Ventricular arrhythmias (VAs) in children are generally idiopathic and have a benign course. Catheter ablation (CA) is increasingly becoming a first-line treatment option in children with idiopathic VAs. Acute ablation success reaches 100% procedures and long-term – 87%. Predictors of outcomes of CA in pediatric patients with idiopathic VAs have not been fully investigated.Aim: To identify predictors of long-term unsuccessful outcomes of CA in pediatric idiopathic VAs.Material and Methods. This retrospective study included 164 children aged 7 to 17 years with idiopathic VAs, who underwent CA from 2011 until 2023 in Almazov National Medical Research Centre. Efficiency was assessed in acute period and 6 months after CA.Results. In this study the acute success was 92% and long-term success was 88,4%. In multivariable models, multifocal VAs (odds ratio: 8,814; 95% CI: 1,943–39,981; p = 0,005), effectiveness of antiarrhythmic therapy (odds ratio: 16,522; 95%CI: 1,959–139,374; p = 0,010) and noninducibility of VAs during procedure (odds ratio: 9,369; 95% CI: 1,400–62,684; 0,021), become predictors of long-term unsuccessful outcomes of CA in pediatric idiopathic VAs.Conclusion. In our study there were identified independent predictors of long-term noneffective CA in children with idiopathic VAs, such as multifocal VAs, effectiveness of antiarrhythmic therapy, and noninducibility of VAs CA. In patients with presence of two or more ventricular foci and the effectivness of antiarrhythmic therapy, prolongate drug therapy may be more preferable.

Machine learning prediction of in-hospital recurrent infarction and cardiac death in patients with myocardial infarction

Background and aimThe aim of the study is to identify statistical patterns in patients with myocardial infarction (MI) during hospitalization that allow predicting the development of acute conditions (recurrent myocardial infarction, cardiac death). MethodsWe identified 3471 episodes of patients treated with a diagnosis acute MI in Almazov National Medical Research Centre. For modelling we selected episodes with acute MI with cardiac surgery operations. Classical machine learning models were chosen as forecasting models: decision trees and ensembles based on them, logistic regression and support vector machine. ResultsThe important signs for predicting recurrent MI were the minimum values of hemoglobin, the echocardiography parameters end systolic volume and pulmonary regurgitation, and the minimum value of leukocyte level. Predictors of lethal outcome during hospitalization were advanced age, high values of leukocytes, low values of hemoglobin, high values of alanine aminotransferase. ConclusionThe obtained results make it possible to predict the development of a lethal outcome and re-infarction based on simple parameters that are easily available in clinical practice.

Index-based assessment of type I diabetes mellitus compensation level influence on oral health condition in adolescents

Relevance. Type I diabetes mellitus is generally recognized as a socially significant disease which directly affects the nature and severity of clinical symptoms of comorbidities, including in the oral cavit y.Material and methods. The study, which was conducted in the Department of Pediatrics of the “V.A. Almazov National Medical Research Center” in St. Petersburg, included 54 patients with type I diabetes mellitus. The mean age of the study group was 15.4 ± 1.27 years. Diabetes duration was 71.2 ± 46 months. The average value of glycated hemoglobin is 8.64 ± 1.69. 11% of patients appeared to have uncontrolled hyperglycemia (HbA1c > 7%). The dental examination included a questionnaire, examination and index evaluation using the Green-Vermillion Hygiene Index (OHI), the PMA index modified by Parma, Russell’s periodontal index (PI) and the DMF index. Statistical data was processed using the JAMOVI 2.3.13 software.Results. The principal component analysis distributed the studied indices by three independent mathematical models-constructs. The binomial regression of the OHI and glycated hemoglobin showed a specificity of 0.903 and a sensitivity of 0.348. Regression analysis of the PI and Hb1Ac showed a specificity of 0.919 and a sensitivity of 0.294.Conclusion. The binomial regression model of dental indices with the glycated hemoglobin index values helped to formulate the Hb1Ac key-point values, which allows for suspecting a highly likely initial stage of gingivitis. Hb1Ac above 8.6 is this value.

Features of the appearance of clinical cardiomyopathies against the background of truncating variants in the <i>ttn</i> gene: a review of the literature and an analysis of the appearance.

Background. To date, the influence of genetic variants in the titin gene on the development of all types of cardiomyopathies has been proven, and this primarily applies to TTNtv, however, the high frequency of these variants in the control population (1–3 %) significantly complicates the determination of the pathogenicity of the detected variants. In addition, due to a significant population frequency (1–3 %) in patients with CMP, variants in the titin gene are often combined with causal variants in other genes, and thus can act as modifiers of the clinical course of the disease and myocardial remodeling.Objective. To study the effect of shortening variants in the titin gene on the clinical course of cardiomyopathies in the presence of causative variants in other genes or etiological factors of the disease.Design and methods. This article will consider three clinical cases of patients diagnosed with CMP who were treated at the Almazov National Medical Research Center. To conduct a genetic examination, next generation sequencing was used with a target cardiopanel to check 108 genes associated with the development of cardiomyopathies, as well as Sanger sequencing to exclude false positive results.Results. During a genetic examination of the studied patients, identified genetic variants in the titin gene led to the syn- thesis of a truncated protein: in all cases, the reason for this was frameshift deletions located in exons with a PSI (Percent Spliced-In) level of 100%. According to the American College of Medical Genetics and Genomics pathogenicity classification, two genetic variants are classified as pathogenic and one is classified as probably pathogenic.Conclusion. In these patients, we found shortening variants (frameshift deletions) in the titin gene, which acted as modifiers of myocardial remodeling.

Desmin Degradation in the Skeletal Muscle of Patients with Chronic Critical Illness

Chronically critically ill patients lose a significant amount of muscle mass during their stay in the intensive care unit, which can have long-term detrimental consequences. This, among other factors, leads to the degradation of the muscle cytoskeleton’s integrity, and at present there are no comprehensive studies that describe the mechanisms b-ehind the development of this process. The purpose of this study was to investigate the signaling processes that contribute to the degradation of desmin in patients with critical illness myopathy (CIM). Incisional muscle biopsies were taken from the soleus muscle from 6 patients undergoing treatment at the A.L. Polenov Russian Research Institute - branch of the Almazov National Medical Research Center, with chronic impairment of consciousness (lasting at least 2 months). Muscle biopsies taken from healthy men using a needle biopsy technique were used as controls. Biopsies were frozen in liquid nitrogen for subsequent Western blot and PCR analysis, as well as immunohistochemical studies. The analysis showed that fibers with an altered histological pattern of desmin were visually identified in 4 out of 6 patients studied. We also observed a significant decrease in desmin content by 69% and a 24% decrease in its mRNA content in patients with CIM. Desmin breakdown may be associated with increased calpain activity and activation of the ubiquitin-proteasome system. In this study, the content of calpain-1 increased under conditions of CIM at the protein level, but remained unchanged at the mRNA level. We observed changes in GSK3-β (Ser9) phosphorylation, which is a crucial step in the d-epolymerization of desmin filaments by calpain-1. A study on ubiquitin ligases revealed a significant 155% increase in the expression of Trim32, along with a decrease in the e-xpression of Atrogin1 and MuRF1. Thus, in this study, we observed a decrease in desmin content under conditions of CIM. The breakdown of desmin may be due to increased phosphorylation by GSK3β and subsequent cleavage by calpain-1. In addition, we observed an increase in the expression of the E3 ubiquitin ligase Trim32, the activity of which, according to literature, also increases after phosphorylation of desmin.

Gestational Trophoblastic Disease with Coexisting Progressing Pregnancy: Personalised Treatment Modalities.

Gestational trophoblastic disease (GTD) coexisting with a steadily progressing pregnancy is an extremely rare condition presented in the literature as a single case or case series of successful delivery. The purpose of this study was to describe five cases of GTD and present possible management strategies for such patients. Clinical data of five pregnancies with coexisting GTD were identified within the Almazov National Medical Research Centre from 2018 to 2021. Three cases of multiple pregnancies with complete hydatidiform moles and two cases of singleton pregnancies with intraplacental choriocarcinoma and invasive hydatidiform moles were identified. Three pregnancies were prolonged and ended with preterm deliveries. Malignant transformation of the GTD accounted for 60% of the cases. The condition of newborns was based on the level of prematurity and functional immaturity, and in all cases, it was aggravated by anemia. GTD coexisting with progressing pregnancy is threatened by the risks of preterm delivery, miscarriage, hemorrhage, and disease progression and requires monitoring in a multidisciplinary clinic experienced in the management of patients with malignant tumors during pregnancy. In cases of prolonged pregnancy against the background of GTD, we suggest the following monitoring during pregnancy: pelvic, abdominal ultrasound/MRI (without contrast), prenatal invasive fetal karyotype testing in cases of singleton pregnancy, lung X-ray/CT with uterine shielding, weekly assessment of β-hCG levels, and dynamic monitoring of the fetus. The following postnatal monitoring should be performed: morphological examination of the placenta, weekly assessment of β-hCG levels up to normalization, then monthly assessment up to six months, and control of β-hCG level of the newborn.

“Epilepsy 90–80–70”: The Intersectoral Global Action Plan on epilepsy and other neurological disorders (2022–2031)

Epilepsy is one of the oldest known nervous system disorders and imposes enormous physical, psychological, social and economic burden on individuals, families and countries due to misunderstanding and stigmatization. These problems are most relevant for developing countries, where up to 85 % of epilepsy patients live. Despite the fact that it is a treatable and preventable disorder, there is a lack of adequate public awareness and understanding of the problems of epilepsy. This article is devoted to the Intersectoral Global Action Plan on epilepsy and other neurological disorders (IGAP) 2022–2031, adopted on 27 May 2022 at the 150th session of WHO’s Executive Board. It provides data on the public and medical importance of epilepsy, the history of the joint initiatives of WHO, the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) aimed at reducing the burden of epilepsy on society and improving public knowledge about neurological disorders. The key provisions of the Intersectoral Global Action Plan on epilepsy and other neurological disorders 2022–2031 are announced. The Epilepsy 90–80–70 cascade target, launched by ILAE and IBE, is presented to inspire decades of action and significantly improve care and treatment for all people living with epilepsy worldwide. The final section is devoted to the evolution of epileptology at Almazov National Medical Research Centre, its present and its prospects.

An artificial intelligence approach for prognosis of COVID-19 course in hospitalized patients

Aim. To create algorithm and risk calculator for predicting the lethal outcome in patients with COVID-19.Materials and methods. Based on machine learning approach mortality risk calculator was developed in Almazov National Medical Research Centre using data of the hospitalised patients with an established diagnosis of COVID-19 (n=4071).Results. This mathematical model, which includes 11 significant features, has been proposed for estimation of fatal outcomes in the Clinical Infectious Hospital named after S.P. Botkin. Some key features were not assessed in most hospitals according to accepted standards of care for COVID-19. So systematic analysis of factors affecting the course of disease in patients (n=2876) were conducted and «urea» and «total protein» were replaced with «sex» and «BMI». Modified algorithm demonstrated high sensitivity and specificity. Conclusion. This calculator is able to predict hospitalisation outcome with high accuracy in patients infected with different strains of SARS-CoV-2. This decision support system may be used for risk stratification and following correct patients routing.

A case of successful orthotopic heart retransplantation in an 11-year-old child

Objective: to present a clinical case of an 11-year-old child who underwent repeat heart transplantation (HT) at Almazov National Medical Research Centre in St. Petersburg, Russia.Materials and methods. A case of successful heart retransplantation in an 11-year-old child with cardiac allograft vasculopathy (CAV) is presented.Results. The postoperative period after heart retransplantation had no significant differences with the postoperative period of primary heart recipients. The complexity of the intraoperative stage was determined by pronounced adhesions. As part of preoperative preparation, the patient underwent chest CT scan, which, in our experience, allows us to evaluate the heart syntopy and, in turn, is an important preparatory stage in planning repeat interventions.Conclusion. Our first experience of cardiac retransplantation in pediatric patients suggests that repeat HT is the most optimal treatment for pediatric patients with CAV and requires more thorough preoperative preparation.

Morphological and Functional Alterations of Respiratory Muscle Performance and Spirometry Parameters in Patients with Congestive Heart Failure

The purpose of the study. To identify structural changes and functional modifications in respiratory muscle performance in patients with congestive heart failure.Materials and methods. We conducted prospective observational study at the V. A. Almazov National Medical Research Center involving 118 subjects: 49 patients with congestive heart failure (CHF-group) and 69 healthy people (control group). NYHA functional classes of II to IV were taken as inclusion criteria in the CHF group, and respiratory diseases, abdominal pathology, morbid obesity, and anemia — as exclusion criteria. Ultrasound imaging was used to assess the structural (thickness) and functional (thickening and excursion indices) diaphragmatic impairments during quiet (resting) and deep breathing. Facemask spirometry was used to assess pulmonary function. Results. Patients with CHF were on average older than 59.0 years (53.0; 70.0) vs. 25.0 years (24.0; 26.0) in the control group, P=0.000001, had excessive body weight — 82.0 (73.0; 95.0) vs. 68.5 (55.0; 84.0) kg, P=0.000005 and higher body mass index — 28.4 (24.3; 31.3) vs 21.8 (19.9; 24.0) kg/m2, P=0.000001, but did not differ in height 173.0 (166.0; 179.0) vs. 170.0 (165.0; 183.0) cm, 0.97.Lower maximum inspiratory volume (MIV): 3000.0 (2300.0; 4000.0) vs. 3684.1 (3392.5; 4310.8) ml, P=0.0006, and negative inspiratory force (NIF) measured as max negative pressure generated by the respiratory muscles: 43.1 (–56.7; –33.0) vs. 53.5 (–58.8; –50.9) mBar, P=0.000082, respectively were found in patients with CHF. The diaphragm was significantly thicker (mm) in patients with CHF during quiet (eupnea) and deep breathing compared to healthy subjects. The thickness at the end of quiet inspiration was 3.0 (2.2; 3.6)/1.9 (1.5; 2.2) in the right hemi-diaphragm, P<0.001; and 3.0 (2.4; 3.5)/1.7 (1.4; 2.0) — in the left, P=0.000001; thickness at the end of quite expiration — 2.2 (1.8; 2.9)/1.5 (1.2; 1.7) in the right dome, P=0.000001; and 2.0 (1.7; 2.5)/1.4 (1.2; 1.5) — in the left, P=0.000001. Thickness at the end of deep inspiration was 5.1 (4.4; 6.1)/4.4 (3.6; 5.1) in the right dome, P=0.0005, and 4.9 (4.2; 6.2)/ 3.7 (3.1; 4.8) — in the left, P=0.000007.The diaphragm thickening index during deep breathing was lower in the CHF group than in the control group: 131.1 (82.5; 181.8) vs. 190.9 (150.0; 240.0) in the right dome, P=0.000004; and 148.8 (112.5; 190.3) vs. 175.2 (130.7; 227.7) — in the left, P=0.03, respectively.Diaphragmatic excursions during quiet breathing were larger in patients with CHF than in healthy controls: 2.3 (1.6; 2.8)/1.7 (1.5; 1.9), P=0.0001 and 1.8 (1.5; 2.2)/1.5 (1.3; 1.9), P=0.03 of the right and left domes, respectively.Conclusion. Congestive heart failure contributes to the development of structural and functional impairments of the diaphragm.

Training of specialists to provide laboratory support in the field of personalized medicine at the Almazov Centre

The system of personnel training for work in modern clinical diagnostic laboratories should meet the challenges that the development of personalized medicine sets for the medical community.Traditionally, departments and courses of clinical laboratory diagnostics in medical higher educational institutions as part of the training of highly qualified personnel — residency and postgraduate studies, carry out such work.The clinical orientation of laboratory diagnostics and its special role in providing personalized medicine urgently requires the close integration with clinical departments, which is implemented in the Almazov National Medical Research Centre within the framework of the University Clinic.