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Introduction: The aim of the study was to assess the differences in key parameters of type 1 diabetes (T1D) control associated with treatment and monitoring modalities including newly introduced hybrid closed-loop (HCL) algorithm in children and adolescents with T1D (CwD) using the data from the population-wide pediatric diabetes registry ČENDA., Methods: CwD younger than 19 years with T1D duration >1 year were included and divided according to the treatment modality and type of CGM used: multiple daily injection (MDI), insulin pump without (CSII) and with HCL function, intermittently scanned continuous glucose monitoring (isCGM), real-time CGM (rtCGM), and intermittent or no CGM (noCGM). HbA1c, times in glycemic ranges, and glucose risk index (GRI) were compared between the groups., Results: Data of a total of 3,251 children (mean age 13.4 ± 3.8 years) were analyzed. 2,187 (67.3%) were treated with MDI, 1,064 (32.7%) with insulin pump, 585/1,064 (55%) with HCL. The HCL users achieved the highest median TIR 75.4% (IQR 6.3) and lowest GRI 29.1 (7.8), both p < 0.001 compared to other groups, followed by MDI rtCGM and CSII groups with TIR 68.8% (IQR 9.0) and 69.0% (7.5), GRI 38.8 (12.5) and 40.1 (8.5), respectively (nonsignificant to each other). These three groups did not significantly differ in their HbA1c medians (51.8 [IQR 4.5], 50.7 [4.5], and 52.7 [5.7] mmol/mol, respectively). NoCGM groups had the highest HbA1c and GRI and lowest TIR regardless of the treatment modality., Conclusion: This population-based study shows that the HCL technology is superior to other treatment modalities in CGM-derived parameters and should be considered as a treatment of choice in all CwD fulfilling the indication criteria., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Early mobilization after total hip replacement (THR) is key for fast recovery but is often limited by pain. Oral enzyme combinations (OECs) have demonstrated anti-inflammatory and pain-relieving effects., Objectives and Design: This prospective, randomized, double-blind, placebo-controlled exploratory trial evaluated the effects of pre- and post-operative use of OEC (90 mg bromelain, 48 mg trypsin, 100 mg rutoside) following elective THR, on post-operative recovery., Methods: Candidates for primary elective cementless THR owing to osteoarthritis were eligible for participation [age ⩾50 years, body mass index 25-35 kg/m 2 , C-reactive protein (CRP) ⩽6 mg/L]. Following randomization to OEC or placebo, intervention started pre-operatively and continued onwards until day 42. Main outcomes included post-operative CRP levels (days 1-7), self-reported hip pain at rest (by 0-10 cm visual analogue scale on post-operative days 1-42), post-operative analgesic use [by cumulative analgesic consumption score (CACS) days 7-42], tolerability and adverse events., Results: Patients ( N  = 34) were recruited from a tertiary orthopaedic hospital in the Czech Republic, of whom 33 completed the study (OEC/placebo: n  = 15/18). Baseline characteristics across the groups were comparable. Compared with placebo, the OEC group had numerically lower CRP levels on post-operative days 1-7, including peak level [mean (standard deviation) OEC versus placebo: 81.4 (28.3) versus 106.7 (63.3) mg/L], which translated into a significant 32% lower CRP area under the curve ( p  = 0.034). The OEC group reported significantly less pain during post-operative days 1-7 versus placebo (analysis of variance treatment × visit [ F (4) = 3.989]; p  = 0.005). Analgesic use was numerically reduced as assessed through an accumulated CACS. No deleterious effects on haemorheological parameters were observed in either group., Conclusions: Pre- and post-operative use of OEC significantly reduced CRP levels and patient self-reported pain. OEC may be an efficacious and safe treatment option to facilitate post-operative recovery following THR., Trial Registration: EudraCT number 2016-003078-41., (© The Author(s), 2023.)

Adaptive immunity changes over an individual’s lifetime, maturing by adulthood and diminishing with old age. Epigenetic mechanisms involving DNA and histone methylation form the molecular basis of immunological memory during lymphocyte development. Monocytes alter their function to convey immune tolerance, yet the epigenetic influences at play remain to be fully understood in the context of lifespan. This study of a healthy genetically homogenous cohort of children, adults and seniors sought to decipher the epigenetic dynamics in B-lymphocytes and monocytes. Variable global cytosine methylation within retro-transposable LINE-1 repeats was noted in monocytes compared to B-lymphocytes across age groups. The expression of the human leukocyte antigen (HLA)-DQ alpha chain gene HLA-DQA1*01 revealed significantly reduced levels in monocytes in all ages relative to B-lymphocytes, as well as between lifespan groups. High melting point analysis and bisulfite sequencing of the HLA-DQA1*01 promoter in monocytes highlighted variable cytosine methylation in children and seniors but greater stability at this locus in adults. Further epigenetic evaluation revealed higher histone lysine 27 trimethylation in monocytes from this adult group. Chromatin immunoprecipitation and RNA pulldown demonstrated association with a novel lncRNA TINA with structurally conserved similarities to the previously recognized epigenetic modifier PARTICLE. Seeking to interpret the epigenetic immunological landscape across three representative age groups, this study focused on HLA-DQA1*01 to expose cytosine and histone methylation alterations and their association with the non-coding transcriptome. Such insights unveil previously unknown complex epigenetic layers, orchestrating the strength and weakening of adaptive immunity with the progression of life.

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To evaluate the development of retinal changes in adolescent patients with diabetes type I (T1DM) with diseases duration more than 10 years, which started before 5 years of age., Methods: The development of the findings on the posterior pole was followed up. The retinal functions were established by means of contrast sensitivity in four space frequencies: 3 cycles/degree (c/deg) (perimacular area), 6 c/deg and 12 c/deg (macular area), and, finally, 18 c/deg (foveola). The central retinal thickness, average retinal thickness of the specified quadrant of macular area, the foveolar depth of its own, and the volume of the perimacular area (perimacular cube volume) were measured by means of optical coherent tomography (OCT)., Material: Altogether 20 patients with diabetes type I meeting the set criteria were examined, and their findings were compared with control group of healthy adolescent people. The values from the control group were used as our normative database., Results: On the retina, there were found, during the diseases course lasting in average 13.3 years, changes of the macular area, especially tortuosity of macular final capillaries and pigmentation with disappearing of foveolar reflex, which, in 20 %, were followed by sporadic hard exsudates of the retina. Difference of the decreased values in adolescent patients, comparing to the control group, was recorded in contrast sensitivity in space frequencies of 3 c/deg (p 0.047) and 12 c/deg (p 0,0497), but statistically significant was the difference in space frequencies of 6 c/deg (p 0.0001) and 18 c/deg (p 0.0001). Using the OCT, no statistically significant difference was found in the central retinal thickness, but the values of foveolar depth in patients with diabetes type I were variable (p 0.0153); in four eyes it was much deeper, and in other four of them it was much shallower. Furthermore, there was higher the average thickness of the retina (p 0.0008) and the volume of the perimacular area (perimacular cube) (p 0,0001)., Conclusion: The findings in eight eyes out of five patients with T1DM were evaluated as diabetic preretinopathy - pre-stage of beginning stage of diabetic retinopathy in central area of the retina from the functional and structural point of view of current pathological changes of contrast sensitivity and OCT. The findings of other three patients were rated as diabetic preretinopathy according to sporadic hard exsudates of the retina and OCT changes, but. until now, without contrast sensitivity changes. The one-year profile of glycated hemoglobin (HbA1c) was higher in patients with diabetic preretinopathy than without the eye involvement, but it was not statistically significant (p 0,0314).Key words: Contrast sensitivity (CS), Spectral Domain Optic Coherence Tomography (SD-OCT), diabetes mellitus type I (T1DM), diabetic preretinopathy (DpR), glycated hemoglobin (HbA1c).

The incidence of type 1 diabetes (DM1) varies greatly among different nations and ethnic groups. Precise mapping of DM1 incidence and its trends is useful in the study of the interaction of genetic and non-genetic factors which influence the manifestation and course of the disease. Important progress has been made in the understanding of the mechanisms of autoimmune diabetes by the study of genes and autoimmune forms of monogenetic diabetes.

Unlabelled: The authors examined repeatedly every year 213 patients (97 boys and young men and 116 girls and young women, age ranged 6-36 years, median: 16.4 years). The diabetes mellitus type I duration at the first eye examination was 0.1 to 26 years (median: 5.9 years), and was diagnosed at the age 2-30 years (median 10.5 years). Changes of the posterior pole and their correlation to functional tests and to metabolic parameters were evaluated in five-years periods since the start of the study (within the fifth year of the study, between years 6-10, 11-15, and over 16 years of the study duration respectively). The beginning changes at the fundus were represented by means of dilatation of the capillaries with their possible obliteration and tortuosity, which was rare (7%) until the 5th year of the disease duration, between 6-10 years it was almost in a half of the patients (43 %), and after 10 years in was present in more than 90% of cases. Changes of the macular structure by means of the irregularity of foveolar reflex and relative retinal thickening without significant macular edema with increased pigmentation of this region appeared rarely after the fifth year (5%) and after 15th year of duration were present in more than two thirds of eyes (65%). Combination of these two findings was considered as diabetic preretinopathy (DpR), and was detected in 9% of eyes until 10 years of duration of diabetes. The number of hard exudates and microaneurysms gradually increased. Signs of non-prolipherative diabetic retinopathy were noticed in 0.5% of cases by means of ophthalmoscopical examination in patients with duration of diabetes type I less than 10 years. After that period, the non-prolipherative diabetic retinopathy was present in 19% of cases, and diabetic preretinopathy in 42%. The contrast sensitivity was examined by means of CSV-1000 instrument in 3, 6, 12 and 18 cycles/degree (c/deg) respectively. Normal values for children 6 years old and older were established in a previous study in a control group of children and teenagers without diabetes and with healthy eyes. In the age range 6 - 10 years the mean threshold values [log] are for: 3 c/deg 1.82; 6 c/deg 2.04; 12 c/deg 1.74; and 18 c/deg 1.29. Since the age of 11 years, normal mean threshold contrast sensitivity values [log] are for: 3 c/deg 1.92; 6 c/deg2.19; 12 c/deg 1.89; and 18 c/deg 1.42. No statistically significant difference was found in respective frequencies at the contrast sensitivity curve formulation. The marginal contrast level with standard deviation less than 0.15 log (range, 0.09 - 0.14), for all spatial frequencies represents for children aged 6 - 10 years the 5th stimulation target, and for those of 11 years of age and older the 6th stimulation target disc of the instrument. The value of pathologically decreased contrast sensitivity increased depending on the duration of the diabetes from 1.5% (up to 5 years of diabetes) to 23% after 15 years of diabetes. The lowest decrease of contrast sensitivity in pathological and border values of space frequencies was found in low-frequency 3 c/deg, which shows the evidence of perifoveolar involvement. No statistical significant difference was found among particular frequencies of low, middle, and higher contrast levels in pathological values of contrast sensitivity, but in case of counting in their border values, the statistical significant difference (p = 0.036) was established between the two frequencies 3 c/deg and 18 c/deg, which is giving the evidence of perifoveolar rather than exactly foveolar changes in scope of diabetes mellitus type I. The total decrease of contrast sensitivity values was determined by the increase of changes' number at the posterior pole by means of diabetic preretinopathy and non-prolipherative diabetic retinopathy mostly after 10 years of diabetes duration. Lowering of the contrast sensitivity by 65% is directly related to already mentioned changes of the macular region structure (MDM) and involvement of the foveola with preserved visual acuity. The decrease of the contrast sensitivity corresponded mostly with the posterior pole finding, and not with the diabetes duration, especially in middle and higher frequencies of 6, 12, and 18 c/deg. Changes in color vision by means of 15 Hue test were found in 7% of followed patients and those were not in direct connection with the disease, but were similar to changes in normal population. The decrease of contrast sensitivity values did not depend on the actual metabolic status of the basic disease (actual blood sugar and Hb A1c levels at the time of the ocular examination), nor with the one year level of compensation of diabetes (level of Hb A1c and microalbuminuria during the one year of the study., Conclusion: The contrast sensitivity examination by means of CSV-1000 device was not time consuming, non invasive for the patients and in case of good cooperation revealed the functional insufficiency of the retina, which was the sign of initial diabetic changes in foveolar and perifoveolar region structure.

Objective: Multiple pituitary hormone deficiency (MPHD) may result from defects of transcription factors that govern early pituitary development. We aimed to establish the prevalence of HESX1, PROP1, and POU1F1 gene defects in a population-based cohort of patients with MPHD and to analyse the phenotype of affected individuals., Design and Methods: Genomic analysis was carried out on 74 children and adults with MPHD from the Czech Republic (including four sibling pairs). Phenotypic data were collected from medical records and referring physicians., Results: One patient carried a heterozygous mutation of POU1F1 (71C > T), and 18 patients (including three sibling pairs) had a PROP1 mutation (genotypes 150delA/301delGA/9/, 301delGA/301-delGA/8/, or 301delGA/349T > A/1/). A detailed longitudinal phenotypic analysis was performed for patients with PROP1 mutations (n = 17). The mean ( +/-s.d.) birth length SDS of these patients (0.12 +/- 0.76) was lower than expected based on their mean ( +/-s.d.) birth weight SDS (0.63 +/- 1.27; P = 0.01). Parental heights were normal. The patients' mean ( +/-s.d.) height SDS declined to -1.5 +/- 0.9, -3.6 +/- 1.3 and -4.1 +/- 1.2 at 1.5, 3 and 5 years of age, respectively. GH therapy, initiated at 6.8 +/- 3.2 years of age (mean dose: 0.022 mg/kg per day), led to substantial growth acceleration in all patients. Mean adult height (n = 7) was normal when adjusted for mid-parental height. ACTH deficiency developed in two out of seven young adult patients., Conclusions: PROP1 defects are a prevalent cause of MPHD. We suggest that testing for PROP1 mutations in patients with MPHD might become standard practice in order to predict risk of additional pituitary hormone deficiencies.

Simultaneous HPLC determination of bromoxynil, ioxynil and dichlobenil, three arylnitrile herbicides, and their metabolic products in soil extracts and microbiological media is described. Limits of detection (LODs) ranged from 0.56 to 3.97 ppb. Slight modification of the mobile phase composition allowed determination of 13 other aromatic nitriles. Assay of aromatic nitrile hydratase, amidase or nitrilase activities is possible by the method developed.