Vosoritide Therapy in Children with Achondroplasia: Early Experience and Practical Considerations for Clinical Practice.

INTRODUCTION: Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide. METHODS: Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations. RESULTS: A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged. CONCLUSION: The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting.

Early GH Treatment Is Effective and Well Tolerated in Children With Turner Syndrome: NordiNet® IOS and Answer Program.

CONTEXT: Despite having normal growth hormone (GH) secretion, individuals with Turner syndrome (TS) have short stature. Treatment with recombinant human GH is recommended for TS girls with short stature. OBJECTIVE: This work aimed to evaluate the effectiveness and safety of Norditropin (somatropin, Novo Nordisk) with up to 10 years of follow-up in children with TS. METHODS: Secondary analysis was conducted of Norditropin data from 2 non-interventional studies: NordiNet® IOS (NCT00960128) and the ANSWER program (NCT01009905). RESULTS: A total of 2377 girls with TS were included in the safety analysis set (SAS), with 1513 in the treatment-naive effectiveness analysis set (EAS). At the start of treatment, 1273 (84%) participants were prepubertal (EAS); mean (SD) age was 8.8 (3.9) years. Mean (SD) dose received at the start of GH treatment was 0.045 (0.011) mg/kg/day (EAS). Mean (SD) baseline insulin-like growth factor-1 (IGF-I) SD score (SDS) was -0.86 (1.52), and mean (SD) duration of GH treatment (SAS) was 3.8 (2.8) years.Height SDS (HSDS) increased throughout follow-up, with near-adult HSDS reached by 264 (17%) participants (mean [SD] -1.99 [0.94]; change from baseline +0.90 [0.85]). During the study, 695 (46%) participants (EAS) entered puberty at a mean (SD) age of 12.7 (1.9) years (whether puberty was spontaneous or induced was unknown). Within the SAS, mean IGF-I SDS (SD) at year 10 was 0.91 (1.69); change from baseline +1.48 (1.70). Serious adverse reactions were reported in 10 participants (epiphysiolysis [n = 3]). CONCLUSION: GH-treated participants with TS responded well, without new safety concerns. Our real-world data are in agreement with previous studies.

Factors Associated With Response to Growth Hormone in Pediatric Growth Disorders: Results of a 5-year Registry Analysis.

Context: Growth hormone (GH) therapy can increase linear growth in patients with growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), and Prader-Willi syndrome (PWS), although outcomes vary by disease state. Objective: To assess growth and identify factors associated with growth response with long-term GH therapy. Methods: Data from pediatric patients with GHD, TS, NS, and PWS obtained at GH treatment initiation (baseline) and annually for 5 years in the ANSWER Program and NordiNet® IOS were analyzed retrospectively. Height standard deviation score (HSDS) was assessed over time, and multivariate analyses determined variables with significant positive effects on growth outcomes in each patient cohort. Results: Data from patients with GHD (n = 12 683), TS (n = 1307), NS (n = 203), and PWS (n = 102) were analyzed. HSDS increased over time during GH treatment in all cohorts. Factors with significant positive effects on ΔHSDS were younger age at GH initiation and lower HSDS at baseline (all cohorts) and higher GH dose (GHD and TS only); sex had no effect in any cohort. The modeling analysis showed that ΔHSDS was greatest in year 1 and attenuated over consecutive years through year 5. Estimated least-squares mean ΔHSDS values at year 5 by cohort were 1.702 (females) and 1.586 (males) in GHD, 1.033 in TS, 1.153 in NS, and 1.392 in PWS. Conclusion: Long-term GH therapy results in large increases in HSDS in patients with GHD, TS, NS, and PWS. Greater gains in HSDS can be obtained with higher GH doses and earlier initiation of treatment.

Diseases Affecting Middle-Aged and Elderly Individuals With Trisomy 21.

BACKGROUND: The life expectancy of individuals with trisomy 21 (Down syndrome, DS) has risen to more than 60 years over the past few decades. As a result, diseases arising in mid and later life have become an issue of major concern in the care of individuals with DS. This article discusses and summarizes, from a multidisciplinary perspective, the diseases commonly affecting this population. METHODS: This narrative review is based on publications identified by a selective literature search, extrapolation of the available evidence, and the authors' personal experience. RESULTS: Robust epidemiological evidence indicates that many different diseases, which are dealt with by many different medical specialties, are more common in individuals with DS. The genetic background of some of these diseases is now understood down to the molecular level, e.g., primary hypothyroidism or Alzheimer's disease in DS. Recent gains in epidemiological and pathophysiological understanding contrast with a dearth of evidence on treatment for most of these disorders. CONCLUSION: In view of the complexity of DS-associated morbidity, it would be desirable for DS-specific multidisciplinary care to be made available to patients with DS.

Concentrations of Soluble Angiotensin Converting Enzyme 2 (sACE2) in Children and Adults with and without COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) pandemic, leads to illness and death. Various risk factors for a severe course, such as higher age, male gender and pre-existing illnesses are known. However, pathophysiological risk factors are largely unclear. Notably, the mild course of disease in children is conspicuous. Angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2 and is a key enzyme in infection. Differences in the distribution of ACE2 can provide insights into different courses of COVID-19. Our aim was to elucidate the role of ACE2 as a pathophysiological risk factor by measuring soluble ACE2 (sACE2) via ELISA in blood samples (lithium-heparin-plasma or serum) of 367 individuals including children and adults with and without COVID-19. sACE2-levels were compared between the groups according to age and sex. In adults and children with COVID-19, sACE2-concentrations are significantly higher compared to healthy individuals. sACE2-levels increase with age and are lower in children compared to adults with COVID-19. Sex doesn't significantly influence sACE2-concentration. It remains unclear whether sACE2 concentrations increase because of the infection and what factors could influence this response. In conclusion, the increase of sACE2-concentration with age could indicate that ACE2 concentrations mirror increased COVID-19 severity.

Type 1 diabetes mellitus and SARS-CoV-2 in pediatric and adult patients - Data from the DPV network.

BACKGROUND: Data on patients with type 1 diabetes mellitus (T1DM) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are sparse. This study aimed to investigate the association between SARS-CoV-2 infection and T1DM. METHODS: Data from the Prospective Diabetes Follow-up (DPV) Registry were analyzed for diabetes patients tested for SARS-CoV-2 by polymerase chain reaction (PCR) in Germany, Austria, Switzerland, and Luxembourg during January 2020-June 2021, using Wilcoxon rank-sum and chi-square tests for continuous and dichotomous variables, adjusted for multiple testing. RESULTS: Data analysis of 1855 pediatric T1DM patients revealed no differences between asymptomatic/symptomatic infected and SARS-CoV-2 negative/positive patients regarding age, new-onset diabetes, diabetes duration, and body mass index. Glycated hemoglobin A1c (HbA1c) and diabetic ketoacidosis (DKA) rate were not elevated in SARS-CoV-2-positive vs. -negative patients. The COVID-19 manifestation index was 37.5% in individuals with known T1DM, but 57.1% in individuals with new-onset diabetes. 68.8% of positively tested patients were managed as outpatients/telemedically. Data analysis of 240 adult T1MD patients revealed no differences between positively and negatively tested patients except lower HbA1c. Of these patients, 83.3% had symptomatic infections; 35.7% of positively tested patients were hospitalized. CONCLUSIONS: Our results indicate low morbidity in SARS-CoV-2-infected pediatric T1DM patients. Most patients with known T1DM and SARS-CoV-2 infections could be managed as outpatients. However, SARS-CoV-2 infection was usually symptomatic if it coincided with new-onset diabetes. In adult patients, symptomatic SARS-CoV-2 infection and hospitalization were associated with age.

MicroRNA-126-3p/5p and Aortic Stiffness in Patients with Turner Syndrome.

Background: Turner Syndrome (TS) is a relatively rare X-chromosomal disease with increased cardiovascular morbidity and mortality. This study aimed to identify whether the circulating miR-126-3p/5p are involved in the pathophysiology of vascular dysfunction in TS. Methods: Using the RT-qPCR, the abundance levels of miR-126-3p and miR-126-5p were determined in 33 TS patients and 33 age-matched healthy volunteers (HVs). Vascular screening, including the assessment of blood pressure, pulse wave velocity, augmentation index, aortic deformation, arterial distensibility, and arterial elastance, was conducted in TS patients and HVs. Results: The abundance levels of miR-126-3p and miR-126-5p were significantly higher in TS patients compared to HVs (p < 0.0001). Within the TS cohort, miR-126-3p/5p correlated significantly with aortic deformation (r = 0.47, p = 0.01; r = 0.48, p < 0.01) and arterial distensibility (r = 0.55, p < 0.01; r = 0.48, p < 0.01). In addition, a significant negative correlation was demonstrated between miR-126-3p and arterial elastance (r = −0.48, p = 0.01). The receiver operating characteristic analysis showed that miR-126-3p and miR-126-5p separated the tested groups with high sensitivity and specificity. Conclusions: The abundance levels of miR-126-3p and miR-126-5p were significantly higher in TS patients compared to HVs. Within the TS cohort, a lower abundance level of miR-126-3p and miR-126-5p was linked with a significantly higher aortic stiffness.

Oral hygiene knowledge versus behavior in children: A questionnaire-based, interview-style analysis and on-site assessment of toothbrushing practices.

OBJECTIVES: Oral hygiene plays an important role in eliminating biofilms and preventing dental caries. However, the implementation of oral health knowledge that children learn from their parents and through school dental health programmes remains poorly studied. This study aimed to investigate oral hygiene knowledge and its practical utilization in children and young adolescents (CYAs) aged 2-15 years. MATERIAL AND METHODS: This was a questionnaire-based, interview-style community survey and on-site practical assessment of CYAs' toothbrushing skills conducted during two 1-day public science-promoting events held at a major German university hospital in consecutive years. CYAs first answered questions on toothbrushing frequency, dental aids used, and dental care. They subsequently underwent diagnostic staining and demonstrated their brushing technique and method. CYAs' responses (percentages) to questionnaire items addressing oral hygiene knowledge and practice, and on-site assessment of toothbrushing skills served as the main outcome measures. RESULTS: Of 244 participating CYAs, 178 (73%) CYAs had no caries experience, the percentage increasing with age from 5% in 2-5-year-olds to 40% in those aged > 10 years. Of 117/244 (48%) indicating that teeth should be brushed three times daily, 80/117 (68%) self-reported twice-daily brushing, 32/117 (27%) reported brushing three times, and 4/117 (3%) stated doing so only once. Although 131/244 (54%) considered that teeth should be brushed for 3 min, 77/131 (59%) self-reported actually doing so and 41/131 (31%) reported brushing for 2min. Seventeen of 42 (40%) participants aged > 10 years showed no systematic brushing method, with 21/42 (50%) failing to clean their teeth completely. Participants aged 6-10 years exhibited the highest proportion (97/134, 72%) of complete cleaning. One hundred and forty-six of 244 (60%) of CYAs knew about floss; 63/134 (43%) reported using it. Good adherence to oral health recommendations (i.e., brushing ≥ 2/day for ≥2min) was observed in 212/244 (87%) CYAs, the remaining 32/244 (13%) exhibiting poor adherence. CONCLUSION: CYAs knew about the importance of oral hygiene and cleaned their teeth frequently. However, translation of their knowledge into practice showed deficiencies. Repeated encouragement to put oral health knowledge into practice is important.

Left atrial remodelling among Turner syndrome patients: novel insights from non-invasive 3D echocardiography.

Background: To assess (I) the left atrial (LA) size, function and (II) the impact of excess weight on the LA and left ventricular (LV) performance in Turner syndrome (TS) patients. Methods: Twenty-five TS patients without congenital heart disease (CHD) and 19 healthy, age-matched controls underwent three-dimensional echocardiography (3DE) for LA volume measurements and two-dimensional speckle tracking echocardiography (2DSTE) for LA strain measurements. LV performance was measured through LV Tei-index, indexed isovolumetric contraction (ICT/√RR interval), indexed relaxation (IVRT/√RR interval) and indexed filling time (FT/√RR interval). Results: Compared to healthy controls, normal-weight TS patients (n=16) displayed significantly increased heart rate (92.88±16.66 vs. 76.53±15.65 bpm; P=0.005), reduced indexed LV filling time (11.67±2.55 vs. 15.16±5.07; P=0.018), reduced 3D maximum LA volume at LV end systole/BSA (16.74±5.00 vs. 19.89±4.32 mL/m2; P=0.05), reduced 3D LA total emptying volume/BSA [10.04 (5.05/18.46) vs. 13.11 (7.69/18.46) mL/m2; P=0.001] and reduced 3D LA active emptying volume/BSA [2.61 (0.1/3.82) vs. 3.44 (1.64/6.37) mL/m2; P=0.006]. Compared to normal-weight TS patients, overweight/obese TS patients (n=9) showed impaired LV Tei-index [0.38 (0.26/0.55) vs. 0.27 (0.07/0.41); P=0.009], prolonged indexed IVRT (2.04±0.72 vs. 1.30±0.64; P=0.015), prolonged indexed ICT [1.96 (1.57/2.73) vs. 1.29 (0.35/2.69); P=0.009] and increased 3D LA active emptying volume/BSA (3.38±1.21 vs. 2.29±1.07 mL/m2; P=0.032). Conclusions: Normal-weight TS patients with increased heart rate and reduced LV filling time display subtle LV diastolic dysfunction in the form of reduced LA reservoir and pump function. Manifested systolic and diastolic LV dysfunction among overweight TS patients is partially compensated through an increase in LA active pump function.

COVID-19 Vaccination of Individuals with Down Syndrome-Data from the Trisomy 21 Research Society Survey on Safety, Efficacy, and Factors Associated with the Decision to Be Vaccinated.

Individuals with Down syndrome (DS) are among the groups with the highest risk for severe COVID-19. Better understanding of the efficacy and risks of COVID-19 vaccines for individuals with DS may help improve uptake of vaccination. The T21RS COVID-19 Initiative launched an international survey to obtain information on safety and efficacy of COVID-19 vaccines for individuals with DS. De-identified survey data collected between March and December 2021 were analyzed. Of 2172 individuals with DS, 1973 (91%) had received at least one vaccine dose (57% BNT162b2), 107 (5%) were unvaccinated by choice, and 92 (4%) were unvaccinated for other reasons. Most participants had either no side effects (54%) or mild ones such as pain at the injection site (29%), fatigue (12%), and fever (7%). Severe side effects occurred in <0.5% of participants. About 1% of the vaccinated individuals with DS contracted COVID-19 after vaccination, and all recovered. Individuals with DS who were unvaccinated by choice were more likely to be younger, previously recovered from COVID-19, and also unvaccinated against other recommended vaccines. COVID-19 vaccines have been shown to be safe for individuals with DS and effective in terms of resulting in minimal breakthrough infections and milder disease outcomes among fully vaccinated individuals with DS.

Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently, neutralising autoantibodies against inflammatory receptor antagonists progranulin and interleukin-1 receptor antagonist (IL-1Ra) were found in adult patients with critical COVID-19. The aim of this study was to investigate the role of such autoantibodies in MIS-C. Methods: In this multicentre, retrospective, cohort study, plasma and serum samples were collected from patients (0-18 years) with MIS-C (as per WHO criteria) treated at five clinical centres in Germany and Spain. As controls, we included plasma or serum samples from children with Kawasaki disease, children with inactive systemic juvenile idiopathic arthritis, and children with suspected growth retardation (non-inflammatory control) across four clinical centres in Germany and Spain (all aged ≤18 years). Serum samples from the CoKiBa trial were used as two further control groups, from healthy children (negative for SARS-CoV-2 antibodies) and children with previous mild or asymptomatic COVID-19 (aged ≤17 years). MIS-C and control samples were analysed for autoantibodies against IL-1Ra and progranulin, and for IL-1Ra concentrations, by ELISA. Biochemical analysis of plasma IL-1Ra was performed with native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signalling reporter assay. Findings: Serum and plasma samples were collected between March 6, 2011, and June 2, 2021. Autoantibodies against IL-1Ra could be detected in 13 (62%) of 21 patients with MIS-C (11 girls and ten boys), but not in children with Kawasaki disease (n=24; nine girls and 15 boys), asymptomatic or mild COVID-19 (n=146; 72 girls and 74 boys), inactive systemic juvenile idiopathic arthritis (n=10; five girls and five boys), suspected growth retardation (n=33; 13 girls and 20 boys), or in healthy controls (n=462; 230 girls and 232 boys). Anti-IL-1Ra antibodies in patients with MIS-C belonged exclusively to the IgG1 subclass, except in one patient who had additional IL-1Ra-specific IgM antibodies. Autoantibodies against progranulin were only detected in one (5%) patient with MIS-C. In patients with MIS-C who were positive for anti-IL-1Ra antibodies, free plasma IL-1Ra concentrations were reduced, and immune-complexes of IL-1Ra were detected. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1Ra was observed in all patients with MIS-C who were positive for anti-IL-1Ra antibodies. Anti-IL-1Ra antibodies impaired IL-1Ra function in reporter cell assays, resulting in amplified IL-1ß signalling. Interpretation: Anti-IL-1Ra autoantibodies were observed in a high proportion of patients with MIS-C and were specific to these patients. Generation of these autoantibodies might be triggered by an atypical, hyperphosphorylated isoform of IL-1Ra. These autoantibodies impair IL-1Ra bioactivity and might thus contribute to increased IL-1ß-signalling in MIS-C. Funding: NanoBioMed fund of the University of Saarland, José Carreras Center for Immuno and Gene Therapy, Dr Rolf M Schwiete Stiftung, Staatskanzlei Saarland, German Heart Foundation, Charity of the Blue Sisters, Bavarian Ministry of Health, the Center for Interdisciplinary Clinical Research at University Hospital Münster, EU Horizon 2020.

Metabolic control during the SARS-CoV-2 lockdown in a large German cohort of pediatric patients with type 1 diabetes: Results from the DPV initiative.

OBJECTIVE: To assess if metabolic control worsened during the SARS-CoV2 lockdown in spring 2020 in youth with type 1 diabetes (T1D) in Germany. METHODS: Data from 19,729 pediatric T1D patients from the diabetes prospective follow-up (DPV) registry were available. Data sets from four time-periods between January 1 and June 30, 2020, were compared with data from the whole year 2019 in the same patient; differences were adjusted for seasonality, increasing age, and longer diabetes duration. HbA1c values from laboratory measurements and estimates derived from continuous glucose monitoring (CGM) were aggregated into a combined glucose indicator (CGI), expressed in analogy to HbA1c. RESULTS: Based on regression models adjusted for differences of sex, age, diabetes duration, and migratory background between the four time-periods, CGI values in 2020 were slightly higher than in 2019, for example, by 0.044% (0.042-0.046) (median [95% CI]) in the second lockdown month, time-period 3. Insulin dose and BMI-SDS were also marginally higher. In 2020, there were fewer hospitalizations (e.g., incidence risk ratio in time-period 3 compared with 2019: 0.52 [95% CI: 0.46-0.58]). In a subgroup of patients reporting CGM data in both years, metrics in 2020 improved: time in target increased, and mean sensor glucose fell, for example, by 2.8% (2.7-2.9), and by 4.4 mg/dl (4.3-4.6) in time-period 3. CONCLUSION: Before, during, and after the lockdown in spring 2020, metabolic control in youth with T1D in Germany did not differ significantly from the preceding year. Further effects of the ongoing pandemic on pediatric T1D patients need to be evaluated.

Age, American Thyroid Association Risk Group, and Response to Therapy Are Prognostic Factors in Children With Differentiated Thyroid Cancer.

CONTEXT: Against the background of increasing incidence, pediatric differentiated thyroid carcinoma (DTC) frequently presents with advanced disease and high recurrence rates while prognosis remains excellent. BACKGROUND: We investigated the use of a pediatric classification and an adult response to therapy risk stratification for pediatric DTC patients and their implications for adaptation of treatment and follow-up. METHODS: Data from patients aged <18 years with a diagnosis of primary DTC, registered with the German Pediatric Oncology Hematology-Malignant Endocrine Tumor registry since 1995, were analyzed. For risk prediction, patients were retrospectively assigned to the American Thyroid Association (ATA) risk groups and evaluated for response to therapy. RESULTS: By October 2019, 354 patients with DTC had been reported (median age at diagnosis 13.7 years, range 3.6-17.9) with lymph node and distant metastases in 74.3% and 24.5%. Mean follow-up was 4.1 years (range 0-20.6). Ten-year overall and event-free survival (EFS) rates were 98.9% and 78.1%. EFS was impaired for patients with lymph node and distant metastases (P < .001), positive postoperative thyroglobulin (P = .006), incomplete resection (P = .002), sequential surgeries to achieve total thyroidectomy (P = .042), invasion of capsule (P < .001) and lymph vessels (P = .005), infiltration of surrounding soft tissues (P < .001), tumor multifocality (P < .001), ATA intermediate- and high-risk group (P < .001), and age <10 years (P < .001). Multivariate analysis revealed age <10 years at diagnosis, ATA high-risk level, and poor response to therapy as significant negative prognostic factors for EFS. CONCLUSION: Age, ATA risk group, and response to therapy emerged as significant prognostic factors for EFS in pediatric patients with DTC, requiring risk-adapted individualized therapy and follow-up.

Cardiovascular safety of growth hormone treatment in Noonan syndrome: real-world evidence.

Objective: The study aims to assess the cardiovascular safety of growth hormone (GH) treatment in patients with Noonan syndrome (NS) in clinical practice. Design: The study design involves two observational, multicentre studies (NordiNet® IOS and the ANSWER Program) evaluating the long-term effectiveness and safety of GH in >38,000 paediatric patients, of which 421 had NS. Methods: Serious adverse events, serious adverse reactions (SARs) and non-serious adverse reactions (NSARs) were reported by the treating physicians. Cardiovascular comorbidities at baseline and throughout the studies were also recorded. Results: The safety analysis set comprised 412 children with NS (29.1% females), with a mean (s.d.) baseline age of 9.29 (3.88) years, treated with an average GH dose of 0.047 (0.014) mg/kg/day during childhood. Cardiovascular comorbidities at baseline were reported in 48 (11.7%), most commonly pulmonary valve stenosis (PVS) and atrial septal defects. Overall, 22 (5.3%) patients experienced 34 safety events. The most common were the NSARs: headache (eight events in seven patients) and arthralgia (five events in three patients). Two SARs occurred in one patient (brain neoplasm and metastases to spine). No cardiovascular safety events were recorded in patients with NS. Five cardiovascular comorbidities in five patients were reported after initiation of GH treatment: three cases of unspecified cardiovascular disease, one ruptured abdominal aortic aneurysm and one PVS. Conclusions: GH treatment had a favourable safety profile in patients with NS, including those with cardiovascular comorbidities. Prospective studies are warranted to systematically assess the safety of GH treatment in patients with NS and cardiovascular disease.

COVID-19 in Children with Down Syndrome: Data from the Trisomy 21 Research Society Survey.

Adults with Down Syndrome (DS) are at higher risk for severe outcomes of coronavirus disease 2019 (COVID-19) than the general population, but evidence is required to understand the risks for children with DS, which is necessary to inform COVID-19 shielding advice and vaccination priorities. We aimed to determine the epidemiological and clinical characteristics of COVID-19 in children with DS. Using data from an international survey obtained from a range of countries and control data from the United States, we compared the prevalence of symptoms and medical complications and risk factors for severe outcomes between DS and non-DS paediatric populations with COVID-19. Hospitalised COVID-19 patients <18 years with DS had a higher incidence of respiratory symptoms, fever, and several medical complications from COVID-19 than control patients without DS <18 years. Older age, obesity, and epilepsy were significant risk factors for hospitalisation among paediatric COVID-19 patients with DS, and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. Mortality rates were low in all paediatric COVID-19 patients (with and without DS), contrasting with previous findings in adults with DS (who exhibit higher mortality than those without DS). Children with DS are at increased risk for more severe presentations of COVID-19. Efforts should be made to ensure the comprehensive and early detection of COVID-19 in this population and to identify children with DS who present comorbidities that pose a risk for a severe course of COVID-19. Our results emphasize the importance of vaccinating children with DS as soon as they become eligible.

Bacterial contamination of forehead skin and surgical mask in aerosol-producing dental treatment.

BACKGROUND: Bacterial contamination of dental professionals' facial skin and protective equipment from treatment-related aerosols and droplets are poorly studied. METHODS: This prospective study analyzed samples from 67 consecutive aerosol-producing dental treatments. Sterile nylon swabs served to collect samples from dental professionals' foreheads before and after exposure. Contact samples were obtained from used surgical masks. Samples were incubated on agar under aerobic and anaerobic conditions. Bacteria were classified by MALDI-TOF mass spectrometry. We determined the frequencies of obligate and facultative oral bacteria and scored bacterial growth (0: none; 1: < 100 colonies; 2: >100 colonies; 3: dense). RESULTS: Bacteria were detected in 95% of skin-swab and 76% of mask samples. Median bacterial scores were 2 for forehead samples before and after treatment, and 1 for masks. Obligate and facultative oral bacteria were more frequent (6% and 30%) in samples from exposed forehead skin, which also showed increased bacterial scores (28%). 5% of samples contained methicillin-sensitive Staphylococcus aureus; 3% contained obligate anaerobes. CONCLUSION: Exposed forehead skin was significantly less contaminated with obligate oral bacteria than expected based on surgical mask findings. Exposed forehead skin showed increased contamination attributable to aerosol-producing procedures. The forehead's physiological skin microbiota may offer some protection against bacterial contamination.

Incidence of COVID-19 and Risk of Diabetic Ketoacidosis in New-Onset Type 1 Diabetes.

OBJECTIVES: With this study, our aim was to quantify the relative risk (RR) of diabetic ketoacidosis at diagnosis of type 1 diabetes during the year 2020 and to assess whether it was associated with the regional incidence of coronavirus disease 2019 (COVID-19) cases and deaths. METHODS: Multicenter cohort study based on data from the German Diabetes Prospective Follow-up Registry. The monthly RR for ketoacidosis in 2020 was estimated from observed and expected rates in 3238 children with new-onset type 1 diabetes. Expected rates were derived from data from 2000 to 2019 by using a multivariable logistic trend regression model. The association between the regional incidence of COVID-19 and the rate of ketoacidosis was investigated by applying a log-binomial mixed-effects model to weekly data with Germany divided into 5 regions. RESULTS: The observed versus expected frequency of diabetic ketoacidosis was significantly higher from April to September and in December (mean adjusted RRs, 1.48-1.96). During the first half of 2020, each increase in the regional weekly incidence of COVID-19 by 50 cases or 1 death per 100 000 population was associated with an increase in the RR of diabetic ketoacidosis of 1.40 (95% confidence interval, 1.10-1.77; P = .006) and 1.23 (1.14-1.32; P < .001), respectively. This association was no longer evident during the second half of 2020. CONCLUSIONS: These findings suggest that the local severity of the pandemic rather than health policy measures appear to be the main reason for the increase in diabetic ketoacidosis and thus the delayed use of health care during the pandemic.

Hydrocortisone dosing in children with classic congenital adrenal hyperplasia: results of the German/Austrian registry.

OBJECTIVE: Treatment of classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH but recommendations regarding dosage/administration are inconsistent. The aim of this study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicenter CAH registry. DESIGN: The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included. METHODS: A custom-made electronic health record software is used at the participating centers. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4. RESULTS: We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (604 boys; median age 7.2 years; 817 salt-wasting phenotype, 471 simple-virilizing phenotype). The mean (lower-upper quartiles) daily HC dose (mg/m² body surface area) was 19.4 (18.9-19.8) for patients <3 months (n = 329), 15.0 (14.6-15.3) for age ≥3-12 months (n = 463), 14.0 (13.7-14.3) for age 1-5.9 years (n = 745), 14.2 (14.0-14.5) for age 6 years to puberty entry (n = 669), and 14.9 (14.6-15.2) during puberty to 18 years (n = 801). Fludrocortisone was administered in 74.1% of patients with a median daily dosage of 88.8 µg. CONCLUSION: Our analyses showed that still a high proportion of children are treated with HC doses higher than recommended. This evaluation provides comprehensive information on nationwide hydrocortisone substitution dosages in children with CAH underlining the benefit of systematic data within a registry to assess daily practice.

Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE "HypoDok").

Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy, we analysed the German registry "HypoDok" for infants with CH, which oversees 1625 patients from 49 participating centres in Germany and Austria from 1997 until today. A total of 357 patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH, n = 24) or continuation (PCH, n = 333) of L-thyroxine (L-T4) treatment at 2 years of age. The receiver operating characteristic (ROC) analysis was performed to identify cutoffs predicting TCH by screening TSH concentrations and L-T4 dosages. Gestational ages, birth weights and prevalence of associated malformations were comparable in both groups. The cutoff screening TSH concentration was 73 mU/L. The cutoff daily L-T4 dosage at 1 year was 3.1 µg/kg (90% sensitivity, 63% specificity; 36 µg/day) and at 2 years of age 2.95 µg/kg (91% sensitivity, 59% specificity; 40 µg/day). At 2 years of age, specificity (71%) increased when both of these parameters were considered together.Conclusion: The decision to continue or cease L-T4 treatment at 2 years of age in CH patients diagnosed in neonatal screening may be based on their screening TSH concentrations and individual L-T4 dosages at 1 and 2 years of age. Thus, TCH and PCH may be distinguished; overtreatment avoided; and affected families reassured. What is Known: • The course of congenital primary hypothyroidism may be transient, causing potential overtreatment. • The dose of l-thyroxine at 1 or 2 years of age may predict a transient course of primary congenital hypothyroidism. What is New: • TSH screening concentration and l-thyroxine dosages at 1 and 2 years of age represent reliable predictors for transient congenital primary hypothyroidism with higher sensitivity and specificity when considered together in order to select eligible patients who qualify for treatment withdrawal.

Management of the First COVID-19 Wave in 45 Pediatric Practices in Saarland.

HINTERGRUND: Das Saarland ist in der ersten Welle der COVID-19-Pandemie eines der am stärksten betroffenen Bundesländer. Niedergelassene Kinder- und Jugendärzte sind für pädiatrische Patienten und ihre Familien erste Ansprechpartner. FRAGESTELLUNG: Darstellung der Herausforderungen und Maßnahmen zur Aufrechterhaltung der Patientenversorgung sowie der Zusammenarbeit während der COVID-19-Pandemie. METHODEN: Internet-basierte Befragung der niedergelassenen Kinder- und Jugendärzte sowie papierbasierte Befragung von nicht-ärztlichem Assistenzpersonal der Kinder- und Jugendarztpraxen im Saarland. ERGEBNISSE: Inhaber von 85% sowie Assistenzpersonal aus 81% der Praxen nahmen teil. Für 71% der Praxisinhaber bzw. 48% des Assistenzpersonals bestand ein erhöhtes persönliches Ausfallrisiko als Risikogruppenangehörige oder aufgrund von Betreuungsverpflichtungen. Es kam aber nur zu wenigen tatsächlichen Ausfällen. 85% halten die Hygiene- und Arbeitsschutzempfehlungen für sinnvoll, aber nur 32% stand bei Pandemiebeginn die notwendige Schutzausrüstung zur Verfügung. 89% der Praxen haben Ihr Praxis- und Patientenmanagement in der Pandemie umgestellt. Es wird ein deutlicher Verbesserungsbedarf in der Pandemievorbereitung (77%) und -bewältigung (61%), aber auch in der Zusammenarbeit mit dem öffentlichen Gesundheitswesen (59%) sowie mit Kindertagesstätten und Schulen (77%) gesehen. SCHLUSSFOLGERUNG: Die erste Welle der Pandemie hat die Praxen vor erhebliche Herausforderungen gestellt, die durch betrieblich-funktionelle Umstrukturierung und -organisation bewältigt wurden. Jedoch wird eine bessere Pandemievorbereitung und Unterstützung bei der Bewältigung einschl. verbesserter Zusammenarbeit mit den Gesundheitsämtern und Kinderbetreuungseinrichtungen gefordert.