Бактериальные инфекции у пациентов детского и подросткового возраста после трансплантации аллогенных гемопоэтических стволовых клеток: этиология, структура, факторы риска

155 children and adolescents who had been diagnosed oncohematological diseases and had undergone allogeneic hemapoetic stem cell transplantation were examined. In post-transplant period 80% of patients developed different bacterial complications. Main risk factors of bacterial infections were acute leukemia (73%), acute «graft versus host disease» (61%), severe infectious complications before HSCT (30%), cytomegaloviral reactivation (51%). Main causative agents were Kl. pneumoniae (15%), Escherichia coli (8%), Enterobacter sp. (7%), Pseudomonas sp. (6,5%), Enterococcus sp. (16,5%), S.еpidermidis (13,5%). Most frequent involved sites are urinary tract (30,6%), lungs (22,5%) and bacteriemia (38,7%). Rise in ciprofloxacin resistans among Entorobactri, aerobic and Gram-positive cocci. General survival rate of patients with bacterial complications was 36,3% (p<0,001). Number of infectious episodes and their severity were statistically significant (both p<0,001) deteriorating factor for general surviral rate.Обследовано 155 пациентов детского и подросткового возраста со злокачественными заболеваниями системы крови после трансплантации аллогенных гемопоэтических стволовых клеток (алло-ТГСК). У 80% больных на разных этапах после алло-ТГСК развились бактериальные осложнения различной степени тяжести. Основными факторами риска бактериальных инфекций были диагноз острого лейкоза (73%), развитие острой «реакции трансплантат против хозяина» (61%), тяжелые инфекционные осложнения в анамнезе до трансплантации (30%), реактивация цитомегаловирусной инфекции (51%). Основные возбудители: Kl. pneumoniae (15%), Escherichia coli (8%), Enterobacter sp. (7%), Pseudomonas sp. (6,5%), Enterococcus sp. (16,5%), S. еpidermidis (13,5%). Наиболее часто возникает поражение мочевыводящих путей (30,6%), легких (22,5%) и бактериемия (38,7%). Отмечен рост резистентности к ципрофлоксацину среди энтеробактерий, аэробной и грам-положительной кокковой флоры. Общая выживаемость больных с развившимися бактериальными осложнениями составила 36,3% (p<0,001). Статистически значимо ухудшает показатели общей выживаемости больных с бактериальными инфекциями количество инфекционных эпизодов (p<0,001) и их тяжесть (p<0,001)

The Methyl-CpG Binding Proteins Mecp2, Mbd2 and Kaiso Are Dispensable for Mouse Embryogenesis, but Play a Redundant Function in Neural Differentiation

The precise molecular changes that occur when a neural stem (NS) cell switches from a programme of self-renewal to commit towards a specific lineage are not currently well understood. However it is clear that control of gene expression plays an important role in this process. DNA methylation, a mark of transcriptionally silent chromatin, has similarly been shown to play important roles in neural cell fate commitment in vivo. While DNA methylation is known to play important roles in neural specification during embryonic development, no such role has been shown for any of the methyl-CpG binding proteins (Mecps) in mice.. No evidence for functional redundancy between these genes in embryonic development or in the derivation or maintenance of neural stem cells in culture was detectable. However evidence for a defect in neuronal commitment of triple knockout NS cells was found.Although DNA methylation is indispensable for mammalian embryonic development, we show that simultaneous deficiency of three methyl-CpG binding proteins genes is compatible with apparently normal mouse embryogenesis. Nevertheless, we provide genetic evidence for redundancy of function between methyl-CpG binding proteins in postnatal mice

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Clinical and biological progress over 50 years in Rett syndrome

In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families

Transsphenoidal endoscopic appro ach in the treat ment of spontaneous cerebrospinal fluid (CSF) leak

Introduction. Spontaneous nasal liquorrhea is a pathological condition associated with defect between nasal cavity and intracranial structures that lead to the expiration of the CSF from the nasal cavity.The objective is to evaluate the effectiveness of endoscopic endonasal approach in the CSF leak treatment.Material and methods. For the period from 2008 to 2018, 38 patients with spontaneous nasal liquorrhea were examined and treated in Pavlov First Saint Petersburg State Medical University, the clinic of neurosurgery of Kirov Medical Institute and Almazov National Medical Research Centre. All patients underwent plastic surgery of the CSF fistula by endoscopic endonasal aproach.Results. Only in 4 cases, there was a large defect, the failure of the closure of which required repeated surgical intervention in 1–2 weeks after the initial operation.Conclusion. The use of autologous tissues (muscle or fat autograft) is the method of choice for repeated surgical plastics of the cerebrospinal fluid fistula or in a large size defect (more than 5 mm)

Risk factors of CMV replication after allogeneic hematopoietic stem cell transplantation in children and adolescents

Risk factors of CMV replication in early period after allo-HSCT (D0‑D100) were – myeloablative conditioning – HR 3.74 (1.67–8.37), р = 0.001; unrelated donor – HR 2.18 (0.86–5.26), р = 0.10; HLA-matched donor – HR 0.24 (0.05–1.06), р = 0,06. In late posttransplant period (from D+100) significant risk factors of CMV-reactivation were (according to multivariate analysis) myeloablative conditioning – HR 13.17 (3.00–57.86), р = 0.001; combination of pretransplant remission of leukemia and using cyclosporine and methotrexate – HR 0.13 (0.03–0.50), р = 0.003; combination of aGVHD and CMV reactivation in early posttransplant period – HR 2.71 (0.86–8.50), р = 0.088; using of bone marrow – HR 0.37 (0.12–1.19), р = 0.095. We revealed the significant association of aGVHD and CMV-reactivation –OR 2.91 (1.07–7.92), р=0.006, and increased rate of cGVHD in patients with CMV replication at third month after allo-HSCT OR – 2.29 (1.03–5.08), р = 0.066. We revealed a tend to decreasing relapse risk in patients who had CMV-replication – HR 0.07 (0.004–1.17), р = 0.06. Cumulative incidence of CMV-disease was 28 %. CMV-disease was lethal in 44 % patients.</p

Bacterial infections in pediatric and adolescent in allogeneic hematopoietic stem cell transplantation recipients: etiology, structure, risk factors

155 children and adolescents who had been diagnosed oncohematological diseases and had undergone allogeneic hemapoetic stem cell transplantation were examined. In post-transplant period 80% of patients developed different bacterial complications. Main risk factors of bacterial infections were acute leukemia (73%), acute «graft versus host disease» (61%), severe infectious complications before HSCT (30%), cytomegaloviral reactivation (51%). Main causative agents were Kl. pneumoniae (15%), Escherichia coli (8%), Enterobacter sp. (7%), Pseudomonas sp. (6,5%), Enterococcus sp. (16,5%), S.еpidermidis (13,5%). Most frequent involved sites are urinary tract (30,6%), lungs (22,5%) and bacteriemia (38,7%). Rise in ciprofloxacin resistans among Entorobactri, aerobic and Gram-positive cocci. General survival rate of patients with bacterial complications was 36,3% (p&lt;0,001). Number of infectious episodes and their severity were statistically significant (both p&lt;0,001) deteriorating factor for general surviral rate