17 research outputs found
Improving the prioritization of children at the emergency department: Updating the Manchester Triage System using vital signs
BACKGROUND: Vital signs are used in emergency care settings in the first assessment of children to identify those that need immediate attention. We aimed to develop and validate vital sign based Manchester Triage System (MTS) discriminators to improve triage of children at the emergency department. METHODS AND FINDINGS: The TrIAGE project is a prospective observational study based on electronic health record data from five European EDs (Netherlands (n = 2), United Kingdom, Austria, and Portugal). In the current study, we included 117,438 consecutive children <16 years presenting to the ED during the study period (2012-2015). We derived new discriminators based on heart rate, respiratory rate, and/or capillary refill time for specific subgroups of MTS flowcharts. Moreover, we determined the optimal cut-off value for each vital sign. The main outcome measure was a previously developed 3-category reference standard (high, intermediate, low urgency) for the required urgency of care, based on mortality at the ED, immediate lifesaving interventions, disposition and resource use. We determined six new discriminators for children <1 year and ≥1 year: "Very abnormal respiratory rate", "Abnormal heart rate", and "Abnormal respiratory rate", with optimal cut-offs, and specific subgroups of flowcharts. Application of the modified MTS reclassified 744 patients (2.5%). Sensitivity increased from 0.66 (95%CI 0.60-0.72) to 0.71 (0.66-0.75) for high urgency patients and from 0.67 (0.54-0.76) to 0.70 (0.58-0.80) for high and intermediate urgency patients. Specificity decreased from 0.90 (0.86-0.93) to 0.89 (0.85-0.92) for high and 0.66 (0.52-0.78) to 0.63 (0.50-0.75) for high and intermediate urgency patients. These differences were statistically significant. Overall performance improved (R2 0.199 versus 0.204). CONCLUSIONS: Six new discriminators based on vital signs lead to a small but relevant increase in performance and should be implemented in the MTS
Comparison of the characteristics at diagnosis and treatment of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries
Background and aims: For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8–10 years for those with a low density lipoprotein cholesterol (LDL-C) >3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. Results: Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3–11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those >10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. Conclusions: The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those >10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations
Toward personalization of asthma treatment according to trigger factors
Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma.Fil: Niespodziana, Katarzyna. Vienna University of Technology; AustriaFil: Borochova, Kristina. Vienna University of Technology; AustriaFil: Pazderova, Petra. Vienna University of Technology; AustriaFil: Schlederer, Thomas. Vienna University of Technology; AustriaFil: Astafyeva, Natalia. Saratov State Medical University; RusiaFil: Baranovskaya, Tatiana. Belarusian Medical Academy of Post Diploma Studies; BielorrusiaFil: Barbouche, Mohamed Ridha. Institut Pasteur de Tunis; TúnezFil: Beltyukov, Evgeny. Ural State Medical University; RusiaFil: Berger, Angelika. Vienna University of Technology; AustriaFil: Borzova, Elena. Russian Medical Academy of Continuous Professional Education; RusiaFil: Bousquet, Jean. MACVIA; Francia. Humboldt-Universität zu Berlin; AlemaniaFil: Bumbacea, Roxana S.. University of Medicine and Pharmacy "Carol Davila"; RumaniaFil: Bychkovskaya, Snezhana. Krasnoyarsk Medical University; RusiaFil: Caraballo, Luis. Universidad de Cartagena; ColombiaFil: Chung, Kian Fan. Imperial College London; Reino Unido. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma; Reino UnidoFil: Custovic, Adnan. Imperial College London; Reino Unido. MRC and Asthma UK Centre in Allergic Mechanisms of Asthma; Reino UnidoFil: Docena, Guillermo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Eiwegger, Thomas. University Of Toronto. Hospital For Sick Children; CanadáFil: Evsegneeva, Irina. Sechenov First Moscow State Medical University; RusiaFil: Emelyanov, Alexander. North-Western Medical University; RusiaFil: Errhalt, Peter. University Hospital Krems and Karl Landsteiner University of Health Sciences; AustriaFil: Fassakhov, Rustem. Kazan Federal University; RusiaFil: Fayzullina, Rezeda. Bashkir State Medical University; RusiaFil: Fedenko, Elena. NRC Institute of Immunology FMBA of Russia; RusiaFil: Fomina, Daria. Sechenov First Moscow State Medical University; RusiaFil: Gao, Zhongshan. Zhejiang University; ChinaFil: Giavina Bianchi, Pedro. Universidade de Sao Paulo; BrasilFil: Gotua, Maia. David Tvildiani Medical University; GeorgiaFil: Greber Platzer, Susanne. Vienna University of Technology; AustriaFil: Hedlin, Gunilla. Karolinska Huddinge Hospital. Karolinska Institutet; Sueci
Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia
BACKGROUND Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin–kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODS We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTS A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was −44.5% in the evolocumab group and −6.2% in the placebo group, for a difference of −38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was −77.5 mg per deciliter (−2.0 mmol per liter) in the evolocumab group and −9.0 mg per deciliter (−0.2 mmol per liter) in the placebo group, for a difference of −68.6 mg per deciliter (−1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONS In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559. opens in new tab.
Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study
Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life
Comparison of the characteristics at diagnosis and treatment of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries
Abstract Background and aims: For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8–10 years for those with a low density lipoprotein cholesterol (LDL-C)>3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. Results: Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3–11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those>10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. Conclusions: The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those>10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations
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
Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries
Background and aims: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. Results: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10 −16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10 −16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). Conclusions: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH
Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries.
Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH
Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries
Background and aims: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece.
Methods: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests.
Results: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10-16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10-16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l).
Conclusions: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.Highlights: LDLR mutations are the most common cause of familial hypercholesterolaemia (FH) in children from 8 European countries; Overall, 279 different LDLR mutations were found in 2531 FH children; The frequency of APOB p.(Arg3527Gln) varied significantly over the 8 countries; APOB-FH was less severe than LDLR-FH for low density lipoprotein-cholesterol (LDL-C) concentration and family onset of coronary heart disease (CHD).The European Register is supported by a grant from the International
Atherosclerosis Society (Pfizer number 24052829). The UK register is
supported by funds from the British Heart Foundation (BHF); HEART
UK, Cardiac Network Co-ordinating Group Wales and the Royal College
of Physicians. SEH is a BHF Professor and is funded by PG08/008, and by
the National Institute for Health Research University College London
Hospitals Biomedical Research Centre. MF is funded by the Fondation
Leducq Transatlantic Networks of Excellence Program grant (no. 14
CVD03). MV is supported by the Ministry of Health, Czechia, project No.
64165, General University Hospital in Prague. TF and LT are supported
by the Ministry of Health, Czechia, grant number NU20-02-00261. The
Austrian FH register has been supported by funds from the Austrian
Heart Foundation and the Tyrolean Regional Government. The Portuguese FH Study has been supported by grants from the Portuguese Science and Technology Foundation and grants from the Portuguese
Cardiology Society. AMM was supported by the Portuguese Science and
Technology Foundation, grant number SFRH/BD/113,017/2015. The
study sponsors had no role in study design, the collection, analysis, and
interpretation of data, the writing of the report or the decision to submit
the manuscript for publication. No honorarium, grant, or other form of
payment was given to anyone to produce the manuscript.info:eu-repo/semantics/publishedVersio