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Introduction Chronic Recurrent Multifocal Osteomyelitis (CRMO) is an autoinflammatory bone disorder with predominantly paediatric onset. Children present with multifocal osteolytic lesions accompanied by bone pain and soft tissue swelling. Patients often exhibit extraosseous co-morbidities such as psoriasis, inflammatory bowel disease, and arthritis. Objectives Comparison of children with two different phenotypes of CRMO defined by presence or absence of extraosseous co-morbidities. Methods Children diagnosed with CRMO at the Motol University Hospital between 2010 and 2020 were retrospectively reviewed, and according to the absence or presence of extraosseous manifestations divided into two cohorts – bone limited CRMO and complex CRMO. The two groups were compared in terms of demographic data, age at disease onset, number and site of bone lesions, laboratory biomarker values, and need of escalation to a second-line therapy. Results Thirty-seven children (30 female, 7 male) with confirmed CRMO were included in the analysis. The mean age at disease onset was 10 years. All but 3 patients presented with multifocal disease. Twenty-three children (62%) had at least one extraosseous manifestation (13 sacroiliitis, 8 inflammatory bowel disease, 6 skin disease [acne, pustulosis, or psoriasis], 7 arthritis). Complex CRMO was associated with a significantly higher ESR rate ( p  = 0.0064) and CRP level ( p  = 0.018). The groups did not differ in number of foci or in age at disease onset. Bone lesion distribution differed between the two groups with significantly more frequent involvement of clavicle ( p  = 0.011) and pelvis ( p  = 0.038) in patients with complex CRMO. Children with complex CRMO more often needed escalation of therapy to DMARDs and biologic agents. Conclusion Our data suggest that CRMO affecting solely the skeleton has milder course compared to complex CRMO with extraskeletal features. Further studies are needed to explore the clinical as well as the patient reported outcomes and promote individually tailored therapeutic strategies in both CRMO phenotypes.

Background To explore type 1 diabetes incidence patterns during the pandemic years 2020 and 2021 in Czechia, to compare them to the trends from the previous decade, and to test its association with indicators of containment measures and of pandemic severity (school closing and the all‐cause excess mortality). Methods The Czech Childhood Diabetes Register is a population‐based incidence register recording patients age 0–14.99 years at diabetes onset. Type 1 diabetes incidence in the pandemic period (April 2020–end of observation Dec 2021) was compared by Poisson regression models to the incidence patterns over the past decade 2010–2019. Results During the pandemic years 2020–2021, 956 children 0–14.99 years old manifested with type 1 diabetes in Czechia. The observed incidence (27.2/100,000/year) was significantly higher than what was expected from the trends over 2010–2019 (incidence rate ratio, IRR = 1.16, 95%CI 1.06–1.28, p = 0.0022). The incidence had a trough during the first lockdown (March–May 2020), then it rose above expected values with no usual summer decrease. The assessed pandemic indicators (school closing and all‐cause excess mortality) were not associated with the incidence levels. Conclusions The COVID‐19 pandemic was associated with a notable upward inflection of the type 1 diabetes incidence curve; the early months of the first lockdown were however hallmarked by a significant dip in new diabetes diagnoses. Long‐term observation will show whether the increased incidence originated only from accelerating an advanced preclinical Stage 2 to overt diabetes, or whether the pandemic triggered new cases of islet autoimmunity.

Objective Increased access to modern technologies is not always accompanied by a decrease in HbA1c. The aim of this study was to identify changes in the proportion of continuous glucose monitoring (CGM) users since 2017, when general reimbursement for CGM became effective in Czechia, and to test whether HbA1c is associated with the percentage of time spent on CGM. Research design and methods All T1D children in the Czech national ČENDA registry (3197 children) were categorized according to their time spent on CGM and associations with age, sex, center size, and HbA1c were tested with calendar year as a stratification factor. Results The proportion of children with any CGM use increased from 37.9% in 2017 to 50.3% in 2018 and 74.8% in 2019. Of the CGM users, 16%, 28%, and 41% of the children spent >70% of their time on CGM over the 3 years of the study period, with an overrepresentation of children in the <10 years age group versus the older age groups (p < 0.001). The proportion of CGM users differed among centers and was positively associated with a large center size (>100 patients) (p < 0.001). HbA1c was negatively associated with the time spent on CGM (p < 0.001). Conclusions A rapid increase in CGM use was reported over the 3 years after general reimbursement. HbA1c was associated with time spent on CGM, a continuing decrease was observed in the >70% category. Reimbursement for CGM likely contributes to the improvement of T1D control at the population level.

Objectives The Czech National Childhood Diabetes Register (ČENDA) is a web‐based nationwide database that collects treatment and outcome data in children and adolescents with diabetes. Here, we present data from the first 5 years of ČENDA (2013‐2017). Methods Data include characteristics of disease onset and annual summaries of key clinical care parameters from every patient treated by participating pediatric diabetes outpatient clinics. Results The database contains data of 4361 children (aged 0‐19 years) from 52 centers (85% of all Czech pediatric patients). Of these, 94% had type 1 diabetes (T1D), 4.5% had genetically proven monogenic or secondary, and 1.5% had type 2 diabetes. In children with T1D, median glycated hemoglobin (HbA1c) decreased throughout the observed period from 66.3 to 61.0 mmol/mol (P < .0001, 95% confidence interval [CI] for change −5.6 to −4 mmol/mol). Consequently, the proportion of children reaching the target therapeutic goal of 58.5 mmol/mol increased from 28% in 2013 to 40% in 2017. The proportion of children treated with insulin pumps (CSII) remained stable over the observed period (25%). In a subanalysis of 1602 patients (long‐standing T1D diagnosed before 2011), the main predictors associated with lower HbA1c were treatment with CSII, male sex and care provided at a large diabetes center (>100 patients). Conclusions A significant continuous decrease in HbA1c was observed in Czech children over the past 5 years. As this improvement was not accompanied by appreciable changes in the mode of therapy, we assume that the establishment of our nationwide register has itself constituted a stimulus towards improvement in the care process.

Childhood-onset type 1 diabetes (T1D) is associated with substantial psychiatric morbidity in later life, but it remains unknown whether these associations are due to common underlying biological mechanisms or the impacts of living with the condition and its treatment. Here, using Czech national register data, we identified children with T1D aged ≤14 years between 1994 and 2007 and estimated the risk of psychiatric disorders up to 24 years later. We found that children diagnosed with T1D had an elevated risk of developing substance use, mood, anxiety and personality disorders, and behavioral syndromes. Conversely, we found that children with T1D had a lower risk of developing psychotic disorders. In Mendelian randomization analysis, we found an association with schizophrenia, which, however, did not persist following multiple testing adjustment. The combined observational and Mendelian randomization evidence suggests that T1D diagnosis in childhood predisposes to far-reaching, extensive psychiatric morbidity, which is unlikely to be explicable by common underlying biological mechanisms. The findings of this study highlight that monitoring and addressing the mental health needs of children with T1D is imperative, whereas glucose dysregulation and/or inflammation implicated in schizophrenia pathogenesis warrants future research.

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-β production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.

Type 1 diabetes (T1D) is an autoimmune disease caused by the loss of self-tolerance toward insulin-producing pancreatic β-cells. Its etiology remains incompletely understood but involves dysregulated T cell responses. Here, we perform single-cell transcriptomic analysis of peripheral blood T cells from children newly diagnosed with T1D, the same children after one year, and healthy donors. We observe that children with diabetes show diminished effector and cytotoxic programs and enhanced stemness-associated gene signature across diverse T cell subsets, especially at diagnosis. In parallel, we detect signs of impaired regulatory capacity in regulatory T cells and regulatory TR3-56 cells. These findings are supported by flow cytometry analysis of the same cohort and reanalysis of publicly available datasets. Overall, our results suggest that T1D is associated with impaired T cell effector differentiation and regulatory T cell dysfunction, both of which may contribute to immune imbalance and loss of self-tolerance. Dysregulation of the T cell compartment is a driving factor in the development of Type 1 diabetes (T1D). Here, the authors present a single-cell gene expression analysis of peripheral blood T cells collected from children with T1D at the time of diagnosis and after one year and report an association with impaired T cell effector differentiation and regulatory T cell dysfunction that contribute to the loss of self-tolerance.

Neutrophils releasing neutrophil extracellular traps (NETs) infiltrate the pancreas prior to type 1 diabetes (T1D) onset; however, the precise nature of their contribution to disease remains poorly defined. To examine how NETs affect immune functions in T1D, we investigated NET composition and their effect on dendritic cells (DCs) and T lymphocytes in T1D children. We showed that T1D patient NET composition differs substantially from that of healthy donors and that the presence of T1D-NETs in a mixed peripheral blood mononuclear cell culture caused a strong shift toward IFNγ-producing T lymphocytes, mediated through activation of innate immunity cells in T1D samples. Importantly, in a monocyte-derived DC (moDC) culture, NETs induced cytokine production, phenotypic change and IFNγ-producing T cells only in samples from T1D patients but not in those from healthy donors. RNA-seq analysis revealed that T1D-NETs presence causes TGFβ downregulation and IFNα upregulation and creates pro-T1D signature in healthy moDCs.

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-β production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.

Type 1 diabetes (T1D) is an autoimmune disorder with unambiguous involvement of both innate and adaptive immune mechanisms in the destruction of pancreatic beta cells. Recent evidence demonstrated that neutrophils infiltrate the pancreas prior to disease onset and therein extrude neutrophil extracellular traps (NETs), web-like structures of DNA and nuclear proteins with a strong pro-inflammatory biologic activity. Our previous work showed that T1D NETs activate dendritic cells, which consequently induce IFNγ-producing Th1 lymphocytes. The aim of this study was to assess direct ex vivo biomarkers of NETosis in the serum of recent onset and long-term pediatric T1D patients, their first-degree relatives and healthy controls. To this end we evaluated serum levels of myeloperoxidase (MPO), neutrophil elastase (NE), proteinase 3 (PR3), protein arginine deiminase 4 (PAD4), LL37 and cell-free DNA-histone complexes in sex- and age-matched cohorts of T1D first-degree relatives, recent-onset T1D patients, and in patients 12 months after clinical manifestation of the disease. Our data shows that disease onset is accompanied by peripheral neutrophilia and significant elevation of MPO, NE, PR3, PAD4 and cell-free DNA-histone complexes. Most biomarkers subsequently decrease but do not always normalize in long-term patients. First-degree relatives displayed an intermediate phenotype, except for remarkably high levels of LL37. Together, this report provides evidence for the presence of ongoing NETosis in pediatric patients with T1D at time of clinical manifestation of the disease, which partly subsides in subsequent years.