The Scientific Advisory board resolution: Implementation of intermittently scanned Continuous Glucose monitoring in clinical practice to improve glycemic control

The Scientific Advisory Board chaired by Academician of the Russian Academy of Sciences, Peterkova V.A. was held 26 of November in Moscow to discuss the possibilities of continuous glucose monitoring technology (CGM) implementation into routine clinical practice in Russia in order to improve glycemic control in patients with diabetes mellitus (DM).The main aims for Advisory board were to determine the most significant indicators and parameters for CGM to be implemented in practice from a practical point of view of LMWH, necessary for implementation in clinical practice, for different patients groups with diabetes.The following questions and topics were raised within the discussion: the importance of additional indicators beyond glycated hemoglobin (HbA1c) for glycemic control assessment in diabetes patients, CGM positioning in International and Russian clinical guidelines, the accuracy of CGM devises and approaches to its assessment, the role of education programs for diabetic patients, including trainings in correct use and data interpretation and analysis of CGM data obtained, clinical evidence analysis for CGM in randomized trials and real world evidence

Lrp4 Modulates Extracellular Integration of Cell Signaling Pathways in Development

The extent to which cell signaling is integrated outside the cell is not currently appreciated. We show that a member of the low-density receptor-related protein family, Lrp4 modulates and integrates Bmp and canonical Wnt signalling during tooth morphogenesis by binding the secreted Bmp antagonist protein Wise. Mouse mutants of Lrp4 and Wise exhibit identical tooth phenotypes that include supernumerary incisors and molars, and fused molars. We propose that the Lrp4/Wise interaction acts as an extracellular integrator of epithelial-mesenchymal cell signaling. Wise, secreted from mesenchyme cells binds to BMP's and also to Lrp4 that is expressed on epithelial cells. This binding then results in the modulation of Wnt activity in the epithelial cells. Thus in this context Wise acts as an extracellular signaling molecule linking two signaling pathways. We further show that a downstream mediator of this integration is the Shh signaling pathway

Distinct Impacts of Eda and Edar Loss of Function on the Mouse Dentition

The Eda-A1-Edar signaling pathway is involved in the development of organs with an ectodermal origin, including teeth. In mouse, mutants are known for both the ligand, Eda-A1 (Tabby), and the receptor, Edar (Downless). The adult dentitions of these two mutants have classically been considered to be similar. However, previous studies mentioned differences in embryonic dental development between EdaTa and Edardl-J mutants. A detailed study of tooth morphology in mutants bearing losses of functions of these two genes thus appears necessary to test the pattern variability induced by the developmental modifications. 3D-reconstructions of the cheek teeth have been performed at the ESRF (Grenoble, France) by X-ray synchrotron microtomography to assess dental morphology. The morphological variability observed in EdaTa and Edardl-J mutants have then been compared in detail. Despite patchy similarities, our detailed work on cheek teeth in EdaTa and Edardl-J mice show that all dental morphotypes defined in Edardl-J mice resolutely differ from those of EdaTa mice. This study reveals that losses of function of Eda and Edar have distinct impacts on the tooth size and morphology, contrary to what has previously been thought. The results indicate that unknown mechanisms of the Eda pathway are implicated in tooth morphogenesis. Three hypotheses could explain our results; an unexpected role of the Xedar pathway (which is influenced by the Eda gene product but not that of Edar), a more complex connection than has been appreciated between Edar and another protein, or a ligand-independent activity for Edar. Further work is necessary to test these hypotheses and improve our understanding of the mechanisms of development

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis

Global Array-Based Transcriptomics from Minimal Input RNA Utilising an Optimal RNA Isolation Process Combined with SPIA cDNA Probes

Technical advances in the collection of clinical material, such as laser capture microdissection and cell sorting, provide the advantage of yielding more refined and homogenous populations of cells. However, these attractive advantages are counter balanced by the significant difficultly in obtaining adequate nucleic acid yields to allow transcriptomic analyses. Established technologies are available to carry out global transcriptomics using nanograms of input RNA, however, many clinical samples of low cell content would be expected to yield RNA within the picogram range. To fully exploit these clinical samples the challenge of isolating adequate RNA yield directly and generating sufficient microarray probes for global transcriptional profiling from this low level RNA input has been addressed in the current report. We have established an optimised RNA isolation workflow specifically designed to yield maximal RNA from minimal cell numbers. This procedure obtained RNA yield sufficient for carrying out global transcriptional profiling from vascular endothelial cell biopsies, clinical material not previously amenable to global transcriptomic approaches. In addition, by assessing the performance of two linear isothermal probe generation methods at decreasing input levels of good quality RNA we demonstrated robust detection of a class of low abundance transcripts (GPCRs) at input levels within the picogram range, a lower level of RNA input (50 pg) than previously reported for global transcriptional profiling and report the ability to interrogate the transcriptome from only 10 pg of input RNA. By exploiting an optimal RNA isolation workflow specifically for samples of low cell content, and linear isothermal RNA amplification methods for low level RNA input we were able to perform global transcriptomics on valuable and potentially informative clinically derived vascular endothelial biopsies here for the first time. These workflows provide the ability to robustly exploit ever more common clinical samples yielding extremely low cell numbers and RNA yields for global transcriptomics

Methodology and implementation of the WHO European Childhood Obesity Surveillance Initiative (COSI)

Establishment of the WHO European Childhood Obesity Surveillance Initiative (COSI) has resulted in a surveillance system which provides regular, reliable, timely, and accurate data on children's weight status—through standardized measurement of bodyweight and height—in the WHO European Region. Additional data on dietary intake, physical activity, sedentary behavior, family background, and school environments are collected in several countries. In total, 45 countries in the European Region have participated in COSI. The first five data collection rounds, between 2007 and 2021, yielded measured anthropometric data on over 1.3 million children. In COSI, data are collected according to a common protocol, using standardized instruments and procedures. The systematic collection and analysis of these data enables intercountry comparisons and reveals differences in the prevalence of childhood thinness, overweight, normal weight, and obesity between and within populations. Furthermore, it facilitates investigation of the relationship between overweight, obesity, and potential risk or protective factors and improves the understanding of the development of overweight and obesity in European primary-school children in order to support appropriate and effective policy responses

Physical Activity, Screen Time, and Sleep Duration of Children Aged 6-9 Years in 25 Countries: An Analysis within the WHO European Childhood Obesity Surveillance Initiative (COSI) 2015-2017

Background: Children are becoming less physically active as opportunities for safe active play, recreational activities, and active transport decrease. At the same time, sedentary screen-based activities both during school and leisure time are increasing. Objectives: This study aimed to evaluate physical activity (PA), screen time, and sleep duration of girls and boys aged 6–9 years in Europe using data from the WHO European Childhood Obesity Surveillance Initiative (COSI). Method: The fourth COSI data collection round was conducted in 2015–2017, using a standardized protocol that included a family form completed by parents with specific questions about their children’s PA, screen time, and sleep duration. Results: Nationally representative data from 25 countries was included and information on the PA behaviour, screen time, and sleep duration of 150,651 children was analysed. Pooled analysis showed that: 79.4% were actively playing for >1 h each day, 53.9% were not members of a sport or dancing club, 50.0% walked or cycled to school each day, 60.2% engaged in screen time for 1 h/day, 8.2–85.6% were not members of a sport or dancing club, 17.7–94.0% walked or cycled to school each day, 32.3–80.0% engaged in screen time for <2 h/day, and 50.0–95.8% slept for 9–11 h/night. Conclusions: The prevalence of engagement in PA and the achievement of healthy screen time and sleep duration are heterogenous across the region. Policymakers and other stakeholders, including school administrators and parents, should increase opportunities for young people to participate in daily PA as well as explore solutions to address excessive screen time and short sleep duration to improve the overall physical and mental health and well-being of children.The authors gratefully acknowledge support from a grant from the Russian Government in the context of the WHO European Office for the Prevention and Control of NCDs. Data collection in the following countries was made possible through funding. Albania: WHO through the Joint Programme on Children, Food Security and Nutrition “Reducing Malnutrition in Children” (the Millennium Development Goals Achievement Fund) and the Institute of Public Health; Bulgaria: Ministry of Health, National Centre of Public Health and Analyses, WHO Regional Office for Europe; Croatia: Ministry of Health, Croatian Institute of Public Health and WHO Regional Office for Europe; Czechia: grants AZV MZČR 17–31670 A and MZČR – RVO EÚ 00023761; Denmark: Danish Ministry of Health; Estonia: Ministry of Social Affairs, Ministry of Education and Research (IUT 42–2), WHO Country Office, and National Institute for Health Development; France: Sante Publique France, the French Agency for Public Health; Georgia: WHO; Ireland: Health Service Executive; Italy: Ministry of Health and Italian National Institute of Health; Kazakhstan: Ministry of Health of the Republic of Kazakhstan and WHO Country Office; Kyrgyzstan: WHO; Latvia: Ministry of Health, Centre for Disease Prevention and Control; Lithuania: Science Foundation of Lithuanian University of Health Sciences and Lithuanian Science Council and WHO; Malta: Ministry of Health; Montenegro: WHO and Institute of Public Health of Montenegro; Poland: National Health Programme, Ministry of Health; Portugal: Ministry of Health Institutions, the National Institute of Health, Directorate General of Health, Regional Health Directorates and the kind technical support from the Center for Studies and Research on Social Dynamics and Health (CEIDSS); Romania: Ministry of Health; San Marino: Health Ministry, Educational Ministry, Social Security Institute and Health Authority; Spain: Spanish Agency for Food Safety and Nutrition (AESAN); Turkmenistan: WHO Country Office in Turkmenistan and Ministry of Health; Turkey: Turkish Ministry of Health and the World Bank

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income&nbsp;countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was &lt;1.1 kg m–2 in the vast majority of&nbsp;countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified