Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.

A pilot study evaluating stress factors during and after the COVID-19 pandemic in Viennese families who have the suspicion of child maltreatment or abuse.

The global population was affected by the unprecedented coronavirus COVID-19 pandemic. The impact of the pandemic on children who suffer child maltreatment has not been explored sufficiently. Child abuse is known to increase in stressful circumstances, and therefore potentially during this pandemic.We aimed to identify and measure the impact of pandemic-related stress in families with a suspicion or confirmed child maltreatment. In addition, other parameters were determined, including resilience factors and family dynamics.We conducted a pilot study at the Medical University of Vienna, Forensic Examination Centre for Children and Adolescents (FOKUS Safeguarding team). Parents, carers and legal guardians of children who were referred for potential child abuse (study group) participated by completing two questionnaires, one year apart, covering the following periods: pre-COVID, during-COVID and post-COVID. Simultaneously, a control group was devised with patients who presented to the Paediatric Emergency Department with unrelated conditions (other than child maltreatment concerns). The questionnaires addressed psychological stress factors and were completed face-to-face and/or via telephone. A total of 35 carers participated, with almost equal numbers in both intervention and control groups.Results show that there was statistically significantly higher stress level perception before and during the pandemic period in the study group. Several families in this group commented on the positive effect of support received from health professionals, especially after the pandemic.

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Which method should we use to determine the hip joint center location in individuals with a high amount of soft tissue?

BACKGROUND: This study investigated the most accurate method for estimating the hip joint center position in clinical 3D gait analysis for young individuals with high amounts of soft tissue. We compared position estimates of five regression-based and two functional methods to the hip joint center position obtained through 3D free-hand ultrasound. METHODS: For this purpose, the data of 14 overweight or obese individuals with a mean age of 13.6 (SD 2.1 yrs) and a BMI of 36.5 (SD 7.1 kg/m2, range 26-52 kg/m2) who underwent standard clinical 3D gait analysis were used. The data of each participant were processed with five regression-based and two functional methods and compared to the hip joint center identified via 3D free-hand ultrasound. FINDINGS: The absolute location errors to 3D free-hand ultrasound for each anatomical plane and the Euclidean distances served as outcomes next to their effects on gait variables. The data suggest that regression-based methods are preferable to functional methods in this population, as the latter demonstrated the highest variability in accuracy with large errors for some individuals. INTERPRETATION: Based on our findings we recommend using the regression method presented by Hara et al. due to its superior overall accuracy of <9 mm on average in all planes and the lowest impact on kinematic and kinetic output variables. We do not recommend using the Harrington equations (single and multiple) in populations with high amounts of soft tissue as they require pelvic depth as input, which can be massively biased when a lot of soft tissue is present around the pelvis.

Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study. METHODS: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks. RESULTS: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related. CONCLUSIONS: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.

Influence of various factors on the legal outcome of cases of child abuse-experiences gathered at an interdisciplinary forensic examination center in Vienna, Austria.

BACKGROUND AND OBJECTIVE: To improve the currently low conviction rate in cases of child abuse a forensic examination center for children and adolescents (FOKUS) was established in Vienna, Austria. Besides a state of the art treatment combined with forensic documentation, one of FOKUS' key goals is to identify potential areas for improvements within the process legal proceedings in cases of child abuse through constant scientific monitoring. The accompanying study at hand includes all patients referred to FOKUS within a two year timeframe (n = 233), monitoring their progression from first contact with the medical professionals from FOKUS to the end of criminal proceedings. A detailed analysis of case files was performed in those cases that were reported to the legal authorities by the clinicians of FOKUS (n = 87). Aim of the study is to investigate which factors contribute to the initiation of legal proceedings and a successful conviction. RESULTS: Multivariate logistic regression analyses showed that main proceedings were opened more often in cases where the offender was an adult (p < 0.001) or admitted his guilt (p < 0.001) and if digital traces were available (p = 0.001) or trial support (p = 0.024) present. Furthermore, the combined occurrence of medical documentation and victim disclosure was related to a higher probability of opening main trials. CONCLUSION: These findings underline how challenging the successful persecution of an offender in cases of child abuse is.

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolemia: an expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is well established since three decades, lowering serum LDL-C levels by more than 70% per session. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment targets and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Macrophage-associated markers of metaflammation are linked to metabolic dysfunction in pediatric obesity.

BACKGPOUND: Metabolically driven chronic low-grade adipose tissue inflammation, so-called metaflammation, is a central feature in obesity. This inflammatory tone is largely driven by adipose tissue macrophages (ATM), which express pro- and anti-inflammatory markers and cytokines such as, e.g., IL-1 receptor antagonist (IL-1RA), CD163 and osteopontin (OPN). Metaflammation ultimately leads to the development of cardiometabolic diseases. This study aimed to evaluate the association between selected adipose tissue macrophage-associated markers and metabolic comorbidities in pediatric obesity. METHODS: From a pediatric cohort with obesity (n = 108), clinically thoroughly characterized including diverse routine blood parameters, oral glucose tolerance test and liver MRI, plasma IL-1RA, soluble (s)CD163 and OPN were measured by ELISA. RESULTS: We observed significantly higher IL-1RA, sCD163, and OPN levels in the plasma of children with metabolic-dysfunction associated fatty liver disease (MAFLD) and metabolic syndrome. Moreover, IL-1RA and sCD163 correlated with hepatic disease and apoptosis markers alanine aminotransferase and CK-18. IL-1RA concentrations additionally correlated with insulin resistance, while children with disturbed glucose metabolism had significantly higher levels of sCD163. CONCLUSION: MAFLD and other metabolic disorders in pediatric patients with obesity are associated with an elevation of adipose tissue macrophage-related inflammation markers.

Cohort analysis of child abuse and neglect cases treated during the initial 2 years of a programme to support hospital-based child protection work in Austria.

OBJECTIVE: To describe characteristics of suspected child abuse and neglect (CAN) cases associated with the decision of paediatric departments (PDs) in Vienna, Austria, to involve services of a regional tertiary child protection service programme (Forensische Kinder- und JugendUntersuchungsStelle, FOKUS). DESIGN: Retrospective cohort analysis of a regional data collection of CAN cases over the first 2 years of FOKUS's operational period (1 July 2015-30 June 2017). SETTING: All CAN cases reported to the PDs of six public hospitals in Vienna. Five of these public hospitals were secondary heath care centres and one was a tertiary healthcare centre. RESULTS: Overall, 231 cases (59.1%) were treated without and 160 (40.9%) with additional involvement of the FOKUS service programme. The odds of a case to be treated without FOKUS involvement were higher if neglect was suspected (OR 3.233, 95% CI 2.024 to 5.279). In contrast, when sexual abuse was suspected, the odds for involvement with FOKUS were significantly higher (OR 7.577, 95% CI 4.580 to 12.879). The odds of being managed with FOKUS services nearly doubled when multiple forms of abuse were suspected (OR 1.926, 95% CI 1.136 to 3.285). The odds for additional FOKUS involvement were significantly lower for patients treated as inpatients (OR 0.239, 95% CI 0.151 to 0.373). CAN patients managed with FOKUS involvement were significantly more often reported to law enforcement (LE) (OR 3.234, 95% CI 2.078 to 5.002). Concurrently, suspected sexual abuse cases and cases reported to LE were more frequently treated in the PD of the tertiary centre than in other PDs (χ2 p<0.001). CONCLUSION: CAN case characteristics significantly influenced if PDs involved a tertiary child protection programme. Suspected sexual abuse, if more than one form of CAN was suspected and cases reported to LE required additional specialist expertise. For suspected neglect involvement of tertiary services seemed less important.

Relative Enhancement in Gadoxetate Disodium-Enhanced Liver MRI as an Imaging Biomarker in the Diagnosis of Non-Alcoholic Fatty Liver Disease in Pediatric Obesity.

Relative enhancement (RE) in gadoxetate disodium (Gd-EOB-DTPA)-enhanced MRI is a reliable, non-invasive method for the evaluation and differentiation between simple steatosis and non-alcoholic steatohepatitis in adults. This study evaluated the diagnostic accuracy of RE in Gd-EOB-DTPA-enhanced liver MRI and hepatic fat fraction (HFF) in unenhanced liver MRI and ultrasound (US) for non-alcoholic fatty liver disease (NAFLD) screening in pediatric obesity. Seventy-four liver US and MRIs from 68 pediatric patients (13.07 ± 2.95 years) with obesity (BMI > BMI-for-age + 2SD) were reviewed with regard to imaging biomarkers (liver size, volume, echogenicity, HFF, and RE in Gd-EOB-DTPA-enhanced MRIs, and spleen size), blood biomarkers, and BMI. The agreement between the steatosis grade, according to HFF in MRI and the echogenicity in US, was moderate. Alanine aminotransferase correlated better with the imaging biomarkers in MRI than with those in US. BMI correlated better with liver size and volume on MRI than in US. In patients with RE < 1, blood biomarkers correlated better with RE than those in the whole sample, with a significant association between gamma-glutamyltransferase and RE (p = 0.033). In conclusion, the relative enhancement and hepatic fat fraction can be considered as non-invasive tools for the screening and follow-up of NAFLD in pediatric obesity, superior to echogenicity on ultrasound.

Respective roles of non-pharmaceutical interventions in bronchiolitis outbreaks: an interrupted time-series analysis based on a multinational surveillance system.

BACKGROUND: Bronchiolitis is a major source of morbimortality among young children worldwide. Non-pharmaceutical interventions (NPIs) implemented to reduce the spread of severe acute respiratory syndrome coronavirus 2 may have had an important impact on bronchiolitis outbreaks, as well as major societal consequences. Discriminating between their respective impacts would help define optimal public health strategies against bronchiolitis. We aimed to assess the respective impact of each NPI on bronchiolitis outbreaks in 14 European countries. METHODS: We conducted a quasi-experimental interrupted time-series analysis based on a multicentre international study. All children diagnosed with bronchiolitis presenting to the paediatric emergency department of one of 27 centres from January 2018 to March 2021 were included. We assessed the association between each NPI and change in the bronchiolitis trend over time by seasonally adjusted multivariable quasi-Poisson regression modelling. RESULTS: In total, 42 916 children were included. We observed an overall cumulative 78% (95% CI -100- -54%; p<0.0001) reduction in bronchiolitis cases following NPI implementation. The decrease varied between countries from -97% (95% CI -100- -47%; p=0.0005) to -36% (95% CI -79-7%; p=0.105). Full lockdown (incidence rate ratio (IRR) 0.21 (95% CI 0.14-0.30); p<0.001), secondary school closure (IRR 0.33 (95% CI 0.20-0.52); p<0.0001), wearing a mask indoors (IRR 0.49 (95% CI 0.25-0.94); p=0.034) and teleworking (IRR 0.55 (95% CI 0.31-0.97); p=0.038) were independently associated with reducing bronchiolitis. CONCLUSIONS: Several NPIs were associated with a reduction of bronchiolitis outbreaks, including full lockdown, school closure, teleworking and facial masking. Some of these public health interventions may be considered to further reduce the global burden of bronchiolitis.

Paediatric patients with heterozygous familial hypercholesterolaemia treated with evolocumab for 80 weeks (HAUSER-OLE): a single-arm, multicentre, open-label extension of HAUSER-RCT.

BACKGROUND: The HAUSER-RCT study showed that 24 weeks of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in paediatric patients with heterozygous familial hypercholesterolaemia was safe and improved lipid parameters compared to placebo. Here, we aimed to evaluate the safety and efficacy of evolocumab in this population for an additional 80 weeks. METHODS: HAUSER-OLE was an 80-week, single-arm, open-label extension of HAUSER-RCT, a randomised controlled trial, and was conducted at 46 centres in 23 countries. Paediatric patients aged 10-17 years with heterozygous familial hypercholesterolaemia who completed 24 weeks of monthly treatment with subcutaneously administered placebo or 420 mg evolocumab in HAUSER-RCT with no serious treatment-emergent adverse events were eligible to enrol in HAUSER-OLE. All patients received open-label subcutaneous evolocumab 420 mg monthly with background statins with or without ezetimibe for 80 additional weeks. The primary endpoint was treatment-emergent adverse events. Efficacy was evaluated by changes in lipids from the baseline of HAUSER-RCT to the end of HAUSER-OLE (104 weeks). This study is registered with ClinicalTrials.gov (NCT02624869) and is now completed. FINDINGS: Between Sept 10, 2016, and Nov 25, 2019, 157 patients were enrolled in HAUSER-RCT and received randomised treatment; 150 continued to HAUSER-OLE, received evolocumab treatment, and were included in the full analysis set, presented here. 146 (97%) of 150 patients completed the open-label extension. The incidence of treatment-emergent adverse events in HAUSER-OLE was 70% (105 of 150). Overall, the most common treatment-emergent adverse events were nasopharyngitis (22 [15%] of 150), headache (14 [9%]), and influenza-like illness (13 [9%]). Serious treatment-emergent adverse events occurred in four (3%) of 150 patients (perforated appendicitis and peritonitis, wrist fracture, anorexia nervosa, and headache); none was considered related to evolocumab. No treatment-emergent adverse events led to treatment discontinuation. At week 80, the mean percentage change from baseline in LDL cholesterol was -35·3% (SD 28·0). INTERPRETATION: After 80 weeks of treatment, evolocumab was safe, well tolerated, and led to sustained reductions in LDL cholesterol in paediatric patients with heterozygous familial hypercholesterolaemia. When lipid goals cannot be achieved with conventional treatments, evolocumab is an effective add-on therapy in paediatric patients. FUNDING: Amgen. TRANSLATIONS: For the French, Spanish, Spanish, Portuguese, Italian and Dutch translations of the abstract see Supplementary Materials section.

Improving the safety of the Manchester triage system for children with congenital heart disease.

This study is a prospective evaluation of the validity of a Manchester triage system (MTS) modification for detecting under-triaged pediatric patients with congenital heart disease (CHD). Children with CHD visiting the emergency unit of the Department of Pediatrics and Adolescent Medicine, University Hospital Vienna in 2014 were included. The MTS modification updated the prioritization of patients with complex syndromic diseases, specific symptoms related to chronic diseases, decreased general condition (DGC), profound language impairment, unknown medical history, or special needs. A four-level outcome severity index based on diagnostic and therapeutic interventions, admission to hospital, and follow-up strategies was defined as a reference standard for the correct clinical classification of the MTS urgency level. Of the 19,264 included children, 940 had CHD. Of this group, 266 fulfilled the inclusion criteria for the modified triage method. The MTS modification was significantly more often applied in under-triaged (65.9%) than correctly or over-triaged (25%) children with CHD (p-value χ2 test < 0.0001, OR 5.848, 95% CI: 3.636-9.6). CONCLUSION: The MTS urgency level upgrade modification could reduce under-triage in children with CHD. Applying a safety strategy concept to the MTS could mitigate under-triage in such a high-risk patient group. WHAT IS KNOWN: • The Manchester triage system is considered to be valid and reliable but tends to over-triage. • A study by Seiger et al. showed poor performance in children with chronic illnesses, especially in children with cardiovascular diseases. WHAT IS NEW: • The MTS modification with one urgency level upgrade could decrease under-triage in children with congenital heart disease. • As reference standard a four level outcome severity index (OSI) was established to include diagnostic investigations, medical interventions, hospital admission or follow up visits in the assessment.

Presentations of children to emergency departments across Europe and the COVID-19 pandemic: A multinational observational study.

BACKGROUND: During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. METHODS AND FINDINGS: Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRRs), using predicted counts for each site as offset to adjust for case-mix differences, were used to compare age groups, diagnoses, and outcomes. Reductions in pediatric ED attendances, hospital admissions, and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (IRR 2.26, 95% CI 1.90 to 2.70, p < 0.001) and in children aged <12 months (12 to <24 months IRR 0.86, 95% CI 0.84 to 0.89; 2 to <5 years IRR 0.80, 95% CI 0.78 to 0.82; 5 to <12 years IRR 0.68, 95% CI 0.67 to 0.70; 12 to 18 years IRR 0.72, 95% CI 0.70 to 0.74; versus age <12 months as reference group, p < 0.001). The lowering of pediatric intensive care admissions was not as great as that of general admissions (IRR 1.30, 95% CI 1.16 to 1.45, p < 0.001). Lower triage urgencies were reduced more than higher triage urgencies (urgent triage IRR 1.10, 95% CI 1.08 to 1.12; emergent and very urgent triage IRR 1.53, 95% CI 1.49 to 1.57; versus nonurgent triage category, p < 0.001). Reductions were highest and sustained throughout the study period for children with communicable infectious diseases. The main limitation was the retrospective nature of the study, using routine clinical data from a wide range of European hospitals and health systems. CONCLUSIONS: Reductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell. TRIAL REGISTRATION: ISRCTN91495258 https://www.isrctn.com/ISRCTN91495258.

Risk Scores for Metabolic Dysfunction-Associated Fatty Liver Disease in Pediatric Obesity.

INTRODUCTION: Early noninvasive detection of incipient liver damage is crucial to prevent long-term adverse health outcomes. A variety of scores to assess liver status have been proposed, mostly for adult populations. Validation of noninvasive hepatic scores to identify children at risk of metabolic dysfunction-associated fatty liver disease (MAFLD) is a gap in research, particularly in youth with severe obesity considering pubertal stage and sex. METHODS: In a well-characterized pediatric population aged 9-19 years (n = 115), 19 published liver scores were analyzed. The area under the receiver operating characteristic curve (AUROC) for determination of MAFLD as assessed by magnetic resonance imaging was calculated. RESULTS: The pediatric indices PNFI, B-AST, and M-APRI and several scores developed in adults significantly differed in children with MAFLD compared to children without, while some established indices did not. Only nonalcoholic fatty liver disease liver fat score (NAFLD-LFS) and the model by Cao et al. [PLoS One. 2013;8(12):e82092] showed acceptable predictive accuracy (AUROC >0.8) independently of pubertal stage and sex. When stratifying for pubertal stage and sex, the GSG-Index was superior in pubertal girls, and NAFLD-LFS performed best in pubertal boys. CONCLUSION: NAFLD-LFS and the model by Cao et al. [PLoS One. 2013;8(12):e82092] were well suited to predict MAFLD in youth with severe obesity. In pubertal children, GSG-Index and NAFLD-LFS performed best in girls and boys, respectively.

Plasma Myostatin Increases with Age in Male Youth and Negatively Correlates with Vitamin D in Severe Pediatric Obesity.

Obesity already causes non-communicable diseases during childhood, but the mechanisms of disease development are insufficiently understood. Myokines such as myostatin and irisin are muscle-derived factors possibly involved in obesity-associated diseases. This explorative study aims to investigate whether myostatin and irisin are associated with metabolic parameters, including the vitamin D status in pediatric patients with severe obesity. Clinical, anthropometric and laboratory data from 108 patients with severe obesity (>97th percentile) aged between 9 and 19 years were assessed. Myostatin, its antagonist follistatin, and irisin, were measured from plasma by ELISA. Myostatin concentrations, particularly in males, positively correlated with age and pubertal stage, as well as metabolic parameters such as insulin resistance. Irisin concentrations correlated positively with HDL and negatively with LDL cholesterol values. For follistatin, the associations with age and pubertal stage were inverse. Strikingly, a negative correlation of myostatin with serum vitamin D levels was observed that remained significant after adjusting for age and pubertal stage. In conclusion, there is an independent association of low vitamin D and elevated myostatin levels. Further research may focus on investigating means to prevent increased myostatin levels in interventional studies, which might open several venues to putative options to treat and prevent obesity-associated diseases.

A Selective Screening Strategy Performed in Pre-School Children and Siblings to Detect Familial Hypercholesterolemia.

(1) Background: Familial hypercholesterolemia (FH), a most common genetic disorder, is underdiagnosed and untreated, especially in children. Individuals with heterozygous familial hypercholesterolemia mostly present without clinical symptoms and are not informed about their high risk for myocardial infarction. Early diagnosis and treatment can prevent premature atherosclerosis and cardiovascular events in patients with FH. The aim was to evaluate the detection rate of pre-school children with FH at school doctor visits in Vienna and, moreover, to examine the frequency of FH identified in the children's siblings by this type of screening. (2) Methods: The selective FH- screening was implemented at the school enrolment examinations in the public primary schools of Vienna. The study period included the school years starting in 2017 to 2020. FH was suspected if a questionnaire on hypercholesterolemia, or cardiovascular events in the family history or on the presence of xanthomas or xanthelasma, was positive. Subsequently, lipid testing was performed on pre-school children and their siblings and elevated lipid screening was defined as either positive by LDL-C ≥ 160 mg/dL and/or non-HDL-C ≥ 190 mg/dL or as borderline by LDL-C ≥ 130 mg/dL and/or non-HDL-C ≥ 160 mg/dL. (3) Results: 66,108 pre-school children participated in the school enrolment examination in 868 public elementary schools in Vienna. In 512 (4%) children, the questionnaire caused suspicion of FH. 344 families agreed their participation in the study. Out of 344 (52% male) tested pre-school children, 20 individuals (40% male) had elevated blood lipid levels with a mean LDL-C of 155 ± 29 mg/dL and a non-HDL-C of 180 ± 24 mg/dL. Out of 291 (44% male) tested siblings, 17 individuals (41% male) showed elevated lipids with a mean LDL-C of 144 ± 19 mg/dL, and a non-HDL-C of 174 ± 19 mg/dL. (4) Conclusions: Screening is the key for early diagnosis and treatment of FH. We have implemented a pre-school screening strategy in cooperation with school physicians. We could identify 20 pre-school children and 17 siblings with an elevated lipid screening test. Full implementation of FH-screening in the pre-school examination visits in Vienna would help to detect high-risk children.

Practice variation across five European paediatric emergency departments: a prospective observational study.

OBJECTIVES: To compare paediatric healthcare practice variation among five European emergency departments (EDs) by analysing variability in decisions about diagnostic testing, treatment and admission. DESIGN AND POPULATION: Consecutive paediatric visits in five European EDs in four countries (Austria, Netherlands, Portugal, UK) were prospectively collected during a study period of 9-36 months (2012-2015). PRIMARY OUTCOME MEASURES: Practice variation was studied for the following management measures: lab testing, imaging, administration of intravenous medication and patient disposition after assessment at the ED. ANALYSIS: Multivariable logistic regression was used to adjust for general patient characteristics and markers of disease severity. To assess whether ED was significantly associated with management, the goodness-of-fit of regression models based on all variables with and without ED as explanatory variable was compared. Management measures were analysed across different categories of presenting complaints. RESULTS: Data from 111 922 children were included, with a median age of 4 years (IQR 1.7-9.4). There were large differences in frequencies of Manchester Triage System (MTS) urgency and selected MTS presentational flow charts. ED was a significant covariate for management measures. The variability in management among EDs was fairly consistent across different presenting complaints after adjustment for confounders. Adjusted OR (aOR) for laboratory testing were consistently higher in one hospital while aOR for imaging were consistently higher in another hospital. Iv administration of medication and fluids and admission was significantly more likely in two other hospitals, compared with others, for most presenting complaints. CONCLUSIONS: Distinctive hospital-specific patterns in variability of management could be observed in these five paediatric EDs, which were consistent across different groups of clinical presentations. This could indicate fundamental differences in paediatric healthcare practice, influenced by differences in factors such as organisation of primary care, diagnostic facilities and available beds, professional culture and patient expectations.

Vascular access for lipid apheresis: a challenge in young children with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (hoFH) is a rare genetic disorder leading to extremely increased LDL-cholesterol (LDL-C), resulting in high cardiovascular risk in early childhood. Lipid apheresis (LA) is an effective treatment and should be started as early as possible to prevent premature cardiovascular events. As peripheral punctures in children can be challenging due to small vessels and anxiety, this study aimed to evaluate feasibility and safety of central venous catheters (CVCs) as vascular access for LA in young children with hoFH. METHODS: Retrospective analysis (2016-2019) on four children with hoFH aged 3-5 years, performing weekly or biweekly LA with a CVC. RESULTS: LDL-C decreased by> 60%. In three children, the use of a permanent CVC for 698, 595, and 411 days, respectively, avoided difficult peripheral access, without the occurrence of occlusion or thrombosis. Unfortunately, one child had recurrent CVC-related infections and needed an arteriovenous fistula from the age of 5. Although the mean dwell time per catheter was 212 days, there were, as expected, severe side effects of early catheter infections with sepsis and accidental self-removal. Starting LA at an early age improved or stabilized carotid intima-media thickness (IMT) in three children. However, IMT did increase in one child caused by intolerance to peripheral punctures and LA interruption. CONCLUSIONS: Permanent CVCs are a viable temporary access choice for LA in young children with hoFH until peripheral venipuncture is practicable. The risk of CVC-related infections needs to be taken into account.

Saliva Sampling for Prospective SARS-CoV-2 Screening of Healthcare Professionals.

OBJECTIVE: The objective of this study was to analyze the feasibility and acceptance of a non-invasive, daily and proactive screening program for SARS-CoV-2 infection employing serial saliva testing, in combination with a digital questionnaire among healthcare providers (HCPs) in a multi-professional setting. DESIGN: This was a prospective cohort study involving HCPs from different units at a single tertiary care center, over a pilot phase of 4 weeks during the first wave of the COVID-19 pandemic from April 18th to June 6th, 2020. SETTING: Pediatric tertiary patient care units, Comprehensive Center for Pediatrics, Medical University of Vienna. SUBJECTS: HCPs from different units, including physicians, nurses, midwives, and administrative staff (with patient contact) were considered eligible for the study. Study participants were working in different settings in our center at varying levels of risk exposure. INTERVENTIONS: Saliva collection from mouth gargle and electronic symptom and exposure monitoring (eSEM) was performed by participants at the onset of each regular clinical shift (day or night shift), using an anonymous ID for matching the results. MEASUREMENTS: RT-PCR of all saliva samples, eSEM, as well as feasibility and acceptance thereof. RESULTS: Two hundred and seventy-five volunteers collected 1,865 saliva samples and responded 1,378 times in the eSEM during a 4-week period. 1,331 (96.7%) responses were that the testing was feasible and acceptable. The most common severe symptom during the 4-week period mentioned by HCPs was headache, reported 54 times (3.9%). Two SARS-CoV-2 positive samples-one of them being associated with symptoms-were identified. The acceptance rate among HCPs was 96.6%. CONCLUSION: Serial saliva screening was a well-accepted and feasible method for monitoring SARS-CoV-2 infectious state in health care professionals. Combination of regular SARS-CoV-2 tests with sequential saliva collection and storage could potentially represent a highly efficient strategy to identify and trace virus positive staff for employee and patient safety.