Dapagliflozin and Empagliflozin in Paediatric Indications: A Systematic Review.

INTRODUCTION: In adults, sodium-glucose cotransporter type 2 inhibitors have revolutionised the treatment of type 2 diabetes mellitus, heart failure, and chronic kidney disease. OBJECTIVE: We aimed to review information on compassionate use, clinical pharmacology, efficacy, and safety of dapagliflozin and empagliflozin in children. METHODS: We conducted a systematic review of published clinical trials, case reports, and observational studies in Medline, Excerpta Medica, and Web of Science databases from inception to September 2023. For the two randomised controlled trials on type 2 diabetes mellitus (T2DM), we implemented a meta-analysis on the primary outcome (mean difference in glycosylated haemoglobin [HbA1c] between intervention and placebo groups). Review Manager (RevMan), version 5.4.1, was used for this purpose. RESULTS: Thirty-five articles (nine case reports, ten case series, one prospective non-controlled trial, four controlled randomised trials, two surveys, six pharmacokinetic studies, and three pharmacovigilance studies) were selected, in which 415 children were exposed to either dapagliflozin or empagliflozin: 189 diabetic patients (mean age 14.7 ± 2.9 years), 32 children with glycogen storage disease type Ib (GSD Ib), glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, or severe congenital neutropenia type 4 (8.5 ± 5.1 years), 47 children with kidney disease or heart failure (11.2 ± 6.1 years), 84 patients in pharmacokinetic studies (15.1 ± 2.3 years), and 63 patients in toxicological series. The effect of dapagliflozin and empagliflozin in T2DM was demonstrated by HbA1c reduction in two randomised trials among a total of 177 adolescents, with a mean HbA1c difference of -0.82% (95% confidence interval -1.34 to -0.29) as compared to placebo (no heterogeneity, I2 = 0%). Dosage ranged between 5 and 20 mg (mean 11.4 ± 3.7) once daily for dapagliflozin and between 5 and 25 mg (mean 15.4 ± 7.4) once daily for empagliflozin. Among the paediatric cases of GSD Ib, empagliflozin 0.1-1.3 mg/kg/day improved neutropenia, infections, and gastrointestinal health. Dapagliflozin (mean dosage 6.9 ± 5.2 mg once daily) was well-tolerated in children with chronic kidney disease and heart failure. Side effects were generally mild, the most frequent being hypoglycaemia in children with GSD Ib (33% of patients) or T2DM (14% of patients) on concomitant hypoglycaemic drugs. Diabetic ketoacidosis is rare in children. CONCLUSION: Early evidence suggests that dapagliflozin and empagliflozin are well tolerated in children. A clinical pharmacology rationale currently exists only for adolescents with diabetes mellitus. PROSPERO REGISTRATION NUMBER: CRD42023438162.

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.

Turner syndrome: skin, liver, eyes, dental and ENT evaluation should be improved.

Introduction: Turner syndrome association with multi-organ system comorbidities highlights the need for effective implementation of follow-up guidelines. We aimed to assess the adequacy of care with international guidelines published in 2007 and 2017 and to describe the phenotype of patients. Methods: In this multicenter retrospective descriptive cohort study, we collected growth and pubertal parameters, associated comorbidities, treatment, and karyotype in patients diagnosed at age <18 years between 1993 and 2022. We assessed age-appropriate recommendation follow-up (children, adolescents and adults) according to the 2007 guidelines if the last visit was before 2017 (18 recommendations) and the 2017 guidelines if the last visit was after 2017 (19 recommendations). Results: We included 68 patients followed at Lausanne University Hospital (n=64) and at Neuchatel Regional Hospital (RHNe) (n=4). 2.9% of patients underwent all recommended investigations.Overall, 68.9 ± 22.5% and 78.5 ± 20.6% of the recommendations were followed, before and after 2017 respectively. High implementation rates were found for height, weight and BMI (100%), cardiac (80 to 100%) and renal (90 to 100%) imaging. Low implementation rates were found for Ear, Nose and Throat (ENT) (56.5%), skin (38.5%), dental (23.1%), ophthalmological (10%) and cholestasis (0 to 29%) assessments, depending on age and time of visit. In adults (n=33), the mean proportion of followed recommendations was lower before than after 2017: 63.5 ± 25.8% vs. 78.7 ± 23.4%, p=0.039. Conclusion: Growth parameters, cardiac and renal imaging are well followed. However, efforts should be made for dental, ENT, ophthalmological, skin and cholestasis assessments. Adequacy of follow-up improved with the quality of transition to adult care.

Diuretics in pediatrics.

Diuretics are frequently prescribed drugs and help managing several pathological conditions, including acute and chronic kidney disease, nephrotic syndrome, congestive heart failure, ascites, systemic and pulmonary hypertension. Diuretic classes include among others osmotic diuretics and carboanhydrase inhibitors, loop diuretics, thiazides, and potassium-sparing diuretics. In this educational article, we aim at reviewing indications, mechanisms of action, and side effects, as well as basic pharmacokinetics considerations and data on diuretics in children, supporting practicing clinicians in choosing (and understanding the background of) the best-suited diuretic regimen for the individual patient. Newer diuretic classes like vaptans and sodium glucose type 2 cotransporter inhibitors, the recent controversies on hydrochlorothiazide, and the issue of diuretic resistance, will also be briefly addressed. CONCLUSION: This educational review offers a didactical overview of diuretics in Pediatrics. WHAT IS KNOWN: • Diuretics are frequently prescribed drugs in both adults and children. • They increase water and sodium excretion, reducing fluid overload. WHAT IS NEW: • This article reviews indications, mechanisms of action, side effects, and basic pharmacokinetics facts on diuretics in Paediatrics. • It also addresses current issues, like the management of diuretic resistance, the recent controversy on hydrochlorothiazide, and the novel classes vaptans and gliflozins.

Consequences of gestational diabetes mellitus on neonatal cardiovascular health: MySweetHeart Cohort study.

BACKGROUND: Hyperglycaemic disorders of pregnancy are associated with offspring cardiovascular alterations. METHODS: MySweetHeart cohort study aimed to assess the effect of maternal gestational diabetes (GDM) on offsprings' cardiovascular health. Newborns underwent clinical and echocardiographic examinations between 2016 and 2020. RESULTS: Compared to mothers without GDM (n = 141), mothers with GDM (n = 123) were more likely to have had GDM in previous pregnancies and had higher weight, BMI, blood glucose, and HbA1c. Newborns of both groups showed similar clinical characteristics. Echocardiography was performed on the 3rd (interquartile range, IQR, 2nd-4th) day of life in 101 offsprings of mothers without and 116 offsprings of mothers with GDM. Left ventricular (LV) mass was similar. Children born to mothers with GDM had a thicker posterior LV wall (z-score +0.15, IQR -0.38/0.62, versus +0.47, IQR -0.11/+1.1, p = 0.004), a smaller end-systolic (1.3 mL, IQR 1.0-1.5 mL, versus 1.4 mL, IQR 1.2-1.8 mL, p = 0.044) but a similar end-diastolic LV volume. They also had shorter tricuspid valve flow duration and aortic valve ejection time, lower tricuspid E-wave and pulmonary valve velocities. CONCLUSIONS: Newborns of mothers with or without GDM had similar clinical characteristics and LV mass. However, some echocardiographic differences were detected, suggesting an altered myocardial physiology among infants of mothers with GDM. REGISTRATION: ClinicalTrials.gov (NCT02872974). IMPACT: Hyperglycaemic disorders of pregnancy are known to be associated with offspring cardiovascular alterations. Clinical characteristics and estimated left ventricular (LV) mass were similar in children issued from mothers with and without gestational diabetes (GDM). Children born to mothers with GDM had a thicker posterior LV wall and a smaller end-systolic LV volume. Although LV mass is not different, myocardial physiology may be altered in these infants. Further studies should investigate the endothelial function of this population and the cardiovascular evolution of these children over time.

The «Amish¼ NM_000256.3:c.3330+2T>G splice variant in MYBPC3 associated with hypertrophic cardiomyopathy is an ancient Swiss mutation.

MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM). Several loss-of-function founder variants have been reported in MYBPC3 from various geographic regions, altogether suggestive of a modest or absent effect of these variants on reproductive fitness. One of them, a MYBPC3 splice variant, NM_000256.3:c.3330+2T > G, was first described in homozygous state in newborns presenting with a severe, recessive form of HCM among the Amish population and was later associated with adult-onset dominant HCM in heterozygous carriers. We here report this splice variant in heterozygous state in eight unrelated Swiss families with HCM, making it the most prevalent cardiomyopathy variant in western Switzerland. This variant was identified in patients using targeted (n = 5) or full-genome sequencing (n = 3). Given the prevalence of this variant in the Old Order Amish, Mennonites and Swiss populations, and given that both Amish and Mennonites founders originated from the Bern Canton in Switzerland, the MYBPC3, NM_000256.3:c.3330+2T > G variant appears to be of Swiss origin. Neighboring regions that hosted the first Amish settlements (Alsace, South Germany) should be on the lookout for that variant. The existence of MYBPC3 founder variants in different populations suggests that individuals with early-onset clinical disease may be the tip of the iceberg of a much larger number of asymptomatic carriers. Alternatively, reproductive fitness could even be slightly increased in some variant carriers to compensate for the reduction of fitness in the more severely affected ones, but this remains to be investigated.

ORCHID (Outcome Registry for CHIldren with severe congenital heart Disease) a Swiss, nationwide, prospective, population-based, neurodevelopmental paediatric patient registry: framework, regulations and implementation.

INTRODUCTION: Congenital heart disease (CHD) is the most frequent birth defect. As survival has significantly improved, attention has turned to neurodevelopmental outcomes of children undergoing heart surgery in early infancy. Since multiple risk factors contribute to neurodevelopmental alterations, a nationwide registry collecting data on medical characteristics, interventions, clinical course and neurodevelopment until school-age is needed to improve the quality of management, identify risk- and protective factors affecting neurodevelopment, and facilitate multicentre trials. METHODS AND ANALYSIS: The Swiss Outcome Registry for CHIldren with severe congenital heart Disease (ORCHID) is a nationwide, prospective, population-based patient registry developed (1) to collect baseline characteristics and clinical data of CHD patients operated with bypass-surgery or hybrid procedures in the first 6 weeks of life in Switzerland, (2) to monitor long-term neurodevelopment, and (3) to relate clinical characteristics and neurodevelopment to identify risk and protective factors in these children. This registry started data collection relating to pregnancy, birth, preoperative course, catheter-based and surgical treatment, postoperative course and reinterventions in 2019. The primary outcome includes standardised neurodevelopmental assessments at 9 to 12 months, 18 to 24 months and 5.5 to 6 years. We expect to include 80 to 100 children per year. Correlation and regression analyses will be used to investigate risk- and protective factors influencing neurodevelopment. ETHICS AND DISSEMINATION OF RESULTS: Swiss ORCHID received support by the Accentus Charitable Foundation, the Anna Mueller Grocholoski Stiftung, the Swiss Society of Paediatric Cardiology, the Verein Kinderherzforschung, and the Corelina - Stiftung für das Kinderherz, and was approved by the cantonal ethics committees. Findings will be presented at national and international scientific meetings, and published in peer-reviewed journals. Results will also be shared with patient organizations, primary health care providers, and public health stakeholders to ensure a widespread dissemination of the results.

Gestational diabetes mellitus and offspring's carotid intima-media thickness at birth: MySweetHeart Cohort study.

OBJECTIVE: Hyperglycaemia during pregnancy is associated with cardiometabolic risks for the mother and the offspring. Mothers with gestational diabetes mellitus (GDM) have signs of subclinical atherosclerosis, including increased carotid intima-media thickness (CIMT). We assessed whether GDM is associated with increased CIMT in the offspring at birth. DESIGN AND SETTING: MySweetHeart Cohort is a prospective cohort study conducted in Switzerland. PARTICIPANTS, EXPOSURE AND OUTCOME MEASURES: This work included pregnant women with and without GDM at 24-32 weeks of gestation and their singleton live-born offspring with data on the primary outcome of CIMT. GDM was diagnosed based on the criteria of the International Association of Diabetes and Pregnancy Study Groups. Offspring's CIMT was measured by ultrasonography after birth (range 1-19 days). RESULTS: Data on CIMT were available for 99 offspring of women without GDM and 101 offspring of women with GDM. Maternal age ranged from 18 to 47 years. Some 16% of women with GDM and 6% of women without GDM were obese. Smoking during pregnancy was more frequent among women with GDM (18%) than among those without GDM (4%). Neonatal characteristics were comparable between the two groups. The difference in CIMT between offspring of women with and without GDM was of 0.00 mm (95% CI -0.01 to 0.01; p=0.96) and remained similar on adjustment for potential confounding factors, such as maternal prepregnancy body mass index, maternal education, smoking during pregnancy, family history of diabetes, as well as offspring's sex, age, and body surface area (0.00 mm (95% CI -0.02 to 0.01; p=0.45)). CONCLUSIONS: We found no evidence of increased CIMT in neonates exposed to GDM. A longer-term follow-up that includes additional vascular measures, such as endothelial function or arterial stiffness, may shed further light on the cardiovascular health trajectories in children born to mothers with GDM. TRIAL REGISTRATION NUMBER: NCT02872974; Pre-results.

Epidemiology of Kawasaki Disease in children in Switzerland: a national prospective cohort study.

AIM OF THE STUDY: Kawasaki disease is a febrile illness which can lead to significant coronary artery lesions. Its incidence varies among countries and is highest in Japan (330.2 children under 5 years old/100,000 per year). Since the epidemiology of Kawasaki disease in Switzerland is unknown, we conducted a national prospective data collection between 2013 and 2017 to describe its incidence, diagnosis, and treatment. METHODS: We collected demographic and clinical data of the children under 17 years old hospitalised with Kawasaki disease in Switzerland between March 2013 and February 2017 using anonymous data collection forms with the help of the Swiss Paediatric Surveillance Unit (SPSU). We defined Kawasaki disease per the 2004 American Heart Association criteria: patients with ≥5 days of fever and ≥4 of the 5 main clinical features were included as complete Kawasaki disease and patients with ≥5 days of fever and <4 of the 5 main clinical features were included as incomplete Kawasaki disease. The incidence was calculated with the data of the Federal Statistical Office of Switzerland, considering permanent residents of the country. The different groups were compared by the unpaired student t-test for continuous variables and Pearson's chi squared test for categorical variables, respectively. RESULTS: We included 175 patients: 60% were boys, with a mean age of 38.2 months. The incidence of Kawasaki disease was 3.1/100,000 [95% CI 2.6-3.7] per year in children under 17 years of age and 8.4/100,000 [95% CI 6.7-10.2] per year in children under 5 years of age. The most frequent clinical signs were a rash (85.4%) and changes of the lips and oral/pharyngeal mucosa (83.4%). The diagnosis of Kawasaki disease was made at a mean of 7.3 days after the first symptom. Echocardiography was abnormal in 52.3%. The treatment with intravenous immunoglobulins (IVIG) and acetylsalicylic acid was administered in accordance with international guidelines. Subgroup analysis showed that children older than 5 years old had significantly more complete Kawasaki disease than the younger ones (78.8% vs 57.4%, p = 0.021). Children with "extreme ages" (<1 year old and >8 years old) were diagnosed later (8.6 (±0.9) vs 7.0 (±0.3) days, p = 0.0129), had longer duration of fever (9.8 (±0.9) vs 8.1 (±0.3) days, p = 0.013) and had more echocardiographic abnormalities (n = 26 (70.3%) vs n = 65 (47.5%), p = 0.014) at diagnosis. One child died during the acute phase of the illness. CONCLUSIONS: The incidence of Kawasaki disease in Switzerland is in the lower range of other European countries.

Arrhythmic Burden of Adult Survivors With Repaired Total Anomalous Pulmonary Venous Connection.

Background: The long-term outcome of adults with repaired total anomalous pulmonary venous connection (TAPVC) is poorly documented. Therefore, the present study aims to provide current clinical data on adult survivors with repaired TAPVC focusing on arrhythmia. Methods: Clinical and imaging data (prevalence and type of arrhythmias, symptoms, surgical and medical treatment, echocardiographic and cardiac magnetic resonance haemodynamic parameters) were retrospectively collected from 8 European centres and compared between patients with and without arrhythmias. Results: Fifty-seven patients were included (age 20 [16-67] years [female 28, 49%]). At the last follow-up, that is, 21 (8-51) years after surgery, 79% and 93% of patients were free of symptoms and cardiac medication, respectively. The prevalence of late arrhythmias was 21%; 9 (16%) patients showed intra-atrial re-entrant tachycardia (IART) and 2 (4%) ventricular arrhythmias. Patients with IART were older (P = 0.018) and 4 (7%) required antiarrhythmic medication. Three patients (5%) underwent an electrophysiological study, and another 3 (5%) underwent pacemaker implantation within 36 months after surgical correction, which were removed in 2 patients after 7 years. Early postoperative arrhythmias (P = 0.005), right ventricular dilatation (P = 0.003), and valvulopathy (P = 0.009) were more often present in patients with late IART. Conclusions: Adult survivors after isolated-TAPVC repair presented a high prevalence of arrhythmias. Age, right ventricular dilatation, early arrhythmias, and valvular lesions are risk factors for IART. Long-term follow-up is important as some of these currently asymptomatic patients will probably develop arrhythmias in the future.

Contexte: Les résultats de santé à long terme chez les adultes ayant subi la correction d'un retour veineux pulmonaire anormal total (RVPAT) sont mal connus. Notre étude vise donc à recueillir des données cli-niques au sujet des patients ayant subi cette intervention et ayant survécu jusqu'à l'âge adulte, en particulier pour ce qui est des arythmies. Méthodologie: Les données d'observation clinique et d'imagerie (la prévalence et le type d'arythmies, les symptômes, les traitements chirurgicaux et médicaux, et les paramètres hémodynamiques obtenus par échographie et par résonance magnétique cardiaque) ont été recueillies de façon rétrospective dans huit centres européens et comparées selon que les patients présentaient ou non une arythmie. Résultats: Cinquante-sept patients ont été retenus (âge médian : 20 [16-67] ans; 28 [49 %] femmes). Au dernier suivi, soit 21 (8-51) ans après l'intervention chirurgicale, 79 % des patients ne présentaient pas de symptômes et 93 % des patients ne prenaient pas de médicaments pour des troubles cardiaques. La prévalence d'arythmies tardives s'élevait à 21 %; neuf patients (16 %) présentaient une tachycardie par réentrée intra-atriale (TRIA) et deux patients (4 %) présentaient des arythmies ventriculaires. Les patients qui présentaient une TRIA étaient plus âgés (P = 0,018) et quatre d'entre eux (7 %) devaient prendre des médicaments antiarythmiques. Trois patients (5 %) avaient subi des études électrophysiologiques et trois autres patients (5 %) avaient subi l'implantation d'un stimulateur cardiaque au cours des 36 mois suivant la correction chirurgicale; le stimulateur cardiaque a été retiré sept ans plus tard dans deux de ces cas. Les arythmies postopératoires précoces (P = 0,005), la dilation du ventricule droit (P = 0,003) et la valvulopathie (P = 0,009) étaient plus fréquentes chez les patients qui présentaient une TRIA tardive. Conclusions: La prévalence d'arythmies chez les patients survivant jusqu'à l'âge adulte après la correction isolée d'un RVPAT était élevée. L'âge, la dilation du ventricule droit, les arythmies précoces et les lésions valvulaires sont des facteurs de risque de TRIA. Il est important d'effectuer un suivi à long terme des patients ayant subi une RVPAT puisque certains d'entre eux, asymptomatiques pour le moment, présenteront sans doute des arythmies dans les années à venir.

Interventions to Decrease Carotid-Intima Media Thickness in Children and Adolescents With Type 1 Diabetes: A Systematic Review and Meta-Analysis.

Introduction: Hyperglycemia is associated with a higher cardiovascular risk, as evidenced by increased carotid-intima media thickness (CIMT) in youth with diabetes. We conducted a systematic review and meta-analysis to assess the effect of pharmacological or non-pharmacological interventions on CIMT in children and adolescents with prediabetes or diabetes. Methods: We conducted systematic searches of MEDLINE, EMBASE, and CENTRAL, together with supplementary searches in trial registers and other sources for studies completed up to September 2019. Interventional studies assessing ultrasound CIMT in children and adolescents with prediabetes or diabetes were considered for inclusion. Where appropriate, data were pooled across studies using random-effect meta-analysis. Quality was assessed using The Cochrane Collaboration's risk-of-bias tool and a CIMT reliability tool. Results: Six studies involving 644 children with type 1 diabetes mellitus were included. No study involved children with prediabetes or type 2 diabetes. Three randomized controlled trials (RCTs) evaluated the effects of metformin, quinapril, and atorvastatin. Three non-randomized studies, with a before-and-after design, evaluated the effects of physical exercise and continuous subcutaneous insulin infusion (CSII). The mean CIMT at baseline ranged from 0.40 to 0.51 mm. The pooled difference in CIMT was -0.01 mm (95% CI: -0.04 to 0.01) for metformin compared to placebo (2 studies; 135 participants; I2: 0%). The difference in CIMT was -0.01 mm (95% CI: -0.03 to 0.01) for quinapril compared to placebo (1 study; 406 participants). The mean change from baseline in CIMT was -0.03 mm (95% CI: -0.14 to 0.08) after physical exercise (1 study; 7 participants). Inconsistent results were reported for CSII or for atorvastatin. CIMT measurement was rated at a higher quality on all reliability domains in 3 (50%) studies. The confidence in results is limited by the low number of RCTs and their small sample sizes, as well as the high risk of bias in before-and-after studies. Conclusions: Some pharmacological interventions may decrease CIMT in children with type 1 diabetes. However, there is great uncertainty with respect to their effects and no strong conclusions can be drawn. Further evidence from larger RCTs is required. Systematic Review Registration: PROSPERO, CRD42017075169.

Risk factors during first 1,000 days of life for carotid intima-media thickness in infants, children, and adolescents: A systematic review with meta-analyses.

BACKGROUND: The first 1,000 days of life, i.e., from conception to age 2 years, could be a critical period for cardiovascular health. Increased carotid intima-media thickness (CIMT) is a surrogate marker of atherosclerosis. We performed a systematic review with meta-analyses to assess (1) the relationship between exposures or interventions in the first 1,000 days of life and CIMT in infants, children, and adolescents; and (2) the CIMT measurement methods. METHODS AND FINDINGS: Systematic searches of Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), and Cochrane Central Register of Controlled Trials (CENTRAL) were performed from inception to March 2019. Observational and interventional studies evaluating factors at the individual, familial, or environmental levels, for instance, size at birth, gestational age, breastfeeding, mode of conception, gestational diabetes, or smoking, were included. Quality was evaluated based on study methodological validity (adjusted Newcastle-Ottawa Scale if observational; Cochrane collaboration risk of bias tool if interventional) and CIMT measurement reliability. Estimates from bivariate or partial associations that were least adjusted for sex were used for pooling data across studies, when appropriate, using random-effects meta-analyses. The research protocol was published and registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42017075169). Of 6,221 reports screened, 50 full-text articles from 36 studies (34 observational, 2 interventional) totaling 7,977 participants (0 to 18 years at CIMT assessment) were retained. Children born small for gestational age had increased CIMT (16 studies, 2,570 participants, pooled standardized mean difference (SMD): 0.40 (95% confidence interval (CI): 0.15 to 0.64, p: 0.001), I2: 83%). When restricted to studies of higher quality of CIMT measurement, this relationship was stronger (3 studies, 461 participants, pooled SMD: 0.64 (95% CI: 0.09 to 1.19, p: 0.024), I2: 86%). Only 1 study evaluating small size for gestational age was rated as high quality for all methodological domains. Children conceived through assisted reproductive technologies (ART) (3 studies, 323 participants, pooled SMD: 0.78 (95% CI: -0.20 to 1.75, p: 0.120), I2: 94%) or exposed to maternal smoking during pregnancy (3 studies, 909 participants, pooled SMD: 0.12 (95% CI: -0.06 to 0.30, p: 0.205), I2: 0%) had increased CIMT, but the imprecision around the estimates was high. None of the studies evaluating these 2 factors was rated as high quality for all methodological domains. Two studies evaluating the effect of nutritional interventions starting at birth did not show an effect on CIMT. Only 12 (33%) studies were at higher quality across all domains of CIMT reliability. The degree of confidence in results is limited by the low number of high-quality studies, the relatively small sample sizes, and the high between-study heterogeneity. CONCLUSIONS: In our meta-analyses, we found several risk factors in the first 1,000 days of life that may be associated with increased CIMT during childhood. Small size for gestational age had the most consistent relationship with increased CIMT. The associations with conception through ART or with smoking during pregnancy were not statistically significant, with a high imprecision around the estimates. Due to the large uncertainty in effect sizes and the limited quality of CIMT measurements, further high-quality studies are needed to justify intervention for primordial prevention of cardiovascular disease (CVD).

Risk Factors for Postprocedural Arterial Ischemic Stroke in Children With Cardiac Disease.

BACKGROUND AND PURPOSE: Cardiac pathologies are the second most frequent risk factor (RF) in children with arterial ischemic stroke (AIS). This study aimed to analyze RFs for AIS in children with cardiac disease and cardiac intervention. METHODS: Data were drawn from the Swiss Neuropediatric Stroke Registry. Patients with cardiac disease and postprocedural AIS registered from 2000 until 2015 were analyzed for the cause of cardiac disease and for potential RFs. RESULTS: Forty-seven out of 78 children with cardiac disease had a cardiac intervention. Of these, 36 presented a postprocedural AIS. Median time from cardiac intervention to symptom onset was 4 days (interquartile range, 2-8.5); time to diagnosis of AIS was 2 days (interquartile range, 0-5.8). Main RFs for postprocedural AIS were hypotension, prosthetic cardiac material, right-to-left shunt, arrhythmias, low cardiac output, and infections. CONCLUSIONS: In children with postprocedural AIS, time to diagnosis was delayed. Most patients presented multiple potentially modifiable RFs as hemodynamic alterations and infections.

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

AIMS: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. METHODS AND RESULTS: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. CONCLUSION: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

Thirty Years of Kawasaki Disease: A Single-Center Study at the University Hospital of Lausanne.

Kawasaki disease is an acute vasculitis with a particular involvement of the coronary arteries. Coronary artery aneurysms develop in 20% of untreated children. It has been shown that early treatment with intravenous immunoglobulins and aspirin decreases this risk to 5%, but the medium to long term prognosis of children with Kawasaki disease is still unclear. To determine the outcome of the disease and risk factors for poor evolution, we reviewed retrospectively the medical records of all patients with a diagnosis of Kawasaki disease at our Institution between 1981 and 2014. Among the 207 patients included in the study, 96 patients had coronary diameter anomalies (46.4%) at diagnosis and children with atypical ages for Kawasaki disease (<1 year or >10 year of age) were more often affected with aneurysms or dilatations. Eighty-four of them had complete regression of coronary aneurysms during the follow-up (87.5%) Absence of immunoglobulins in the acute phase was associated with less regression rate (57.1 vs. 92.2%), and boys had greater z-scores at last echocardiography, statistically significant for the left anterior descending artery. We found rare complications after the acute phase documented in our patient charts (only 3.8%). Recurrence of the disease occurred in 5 children (2.4%) and myocardial ischemia in 3 patients (1.4%), all with initial coronary aneurysm. Conclusion: Medium to long term prognosis after Kawasaki disease is excellent. Boys, patients not treated with immunoglobulins or outside the usual age range are more at risk for an unfavorable outcome.

Improving mental health and physiological stress responses in mothers following traumatic childbirth and in their infants: study protocol for the Swiss TrAumatic biRth Trial (START).

INTRODUCTION: Emergency caesarean section (ECS) qualifies as a psychological trauma, which may result in postnatal post-traumatic stress disorder (PTSD). Maternal PTSD may not only have a significant negative impact on mother-infant interactions, but also on long-term infant development. The partner's mental health may also affect infant development. Evidence-based early interventions to prevent the development of postpartum PTSD in mothers are lacking. Immediately after a traumatic event, memory formation is vulnerable to interference. There is accumulating evidence that a brief behavioural intervention including a visuospatial task may result in a reduction in intrusive memories of the trauma. METHODS AND ANALYSIS: This study protocol describes a double-blind multicentre randomised controlled phase III trial testing an early brief maternal intervention including the computer game 'Tetris' on intrusive memories of the ECS trauma (≤1 week) and PTSD symptoms (6 weeks, primary outcome) of 144 women following an ECS. The intervention group will carry out a brief behavioural procedure including playing Tetris. The attention-placebo control group will complete a brief written activity log. Both simple cognitive tasks will be completed within the first 6 hours following traumatic childbirth. The intervention is delivered by midwives/nurses in the maternity unit.The primary outcome will be differences in the presence and severity of maternal PTSD symptoms between the intervention and the attention-placebo control group at 6 weeks post partum. Secondary outcomes will be physiological stress and psychological vulnerability, mother-infant interaction and infant developmental outcomes. Other outcomes will be psychological vulnerability and physiological regulation of the partner and their bonding with the infant, as well as the number of intrusive memories of the event. ETHICS AND DISSEMINATION: Ethical approval was granted by the Human Research Ethics Committee of the Canton de Vaud (study number 2017-02142). Dissemination of results will occur via national and international conferences, in peer-reviewed journals, public conferences and social media. TRIAL REGISTRATION NUMBER: NCT03576586.

Risk factors and determinants of carotid intima-media thickness in children: protocol for a systematic review and meta-analysis.

INTRODUCTION: Carotid intima-media thickness (CIMT) is a surrogate marker of atherosclerosis that is measured in adults and children to better understand the natural history of cardiovascular disease (CVD). In adults, CIMT is predictive of myocardial infarction and stroke. In children and adolescents, CIMT is used to assess vascular changes in the presence of CVD risk factors (obesity, hypertension, smoking, etc) or clinical conditions associated with a high risk for premature CVD. However, there is no comprehensive overview, in a life-course epidemiology perspective, of the risk factors and determinants of CIMT in children. It is also important to evaluate between-study differences in CIMT measurement methods and take them into consideration when drawing conclusions. Our objective is to systematically review the evidence on the relationship between CIMT and prenatal and postnatal exposures or interventions in children, as well as documenting and discussing the CIMT measurement methods. METHODS AND ANALYSIS: Systematic searches of the Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica (EMBASE)and Central Register of Controlled Trials (CENTRAL) databases will be conducted. The reference lists and other literatures sources will be browsed. Observational and experimental studies in children from birth up to 18 years will be included. Prenatal and postnatal exposures or interventions assessed in relationship with CIMT will be considered for inclusion. Examples might include gestational age, obesity, hypertension, tobacco exposure, specific at-risk conditions (chronic kidney disease, diabetes, etc) or statin treatment. The outcome will be CIMT assessed by ultrasonography. The setting, scanning and measurement methods for each included study will be described in detail. Results will be synthesised descriptively and, if appropriate, will be pooled across studies to perform meta-analyses. Separate meta-analyses for each exposure or intervention type will be conducted. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal. A report will be prepared for clinicians and other healthcare decision-makers. PROSPERO REGISTRATION NUMBER: CRD42017075169.

Echocardiographic Evaluation of Ventricular Function-For the Neonatologist and Pediatric Intensivist.

In the neonatal and pediatric intensive care setting, bedside cardiac ultrasound is often used to assess ventricular dimensions and function. Depending upon the underlying disease process, it is necessary to be able to evaluate the systolic and diastolic function of left and or right ventricles. The systolic function of left ventricle is mostly assessed qualitatively on visual inspection "eye-balling" and quantitatively by measuring circumferential fraction shortening or calculating the ejection fraction by Simpson's planimetry. The assessment of left ventricular diastolic function relies essentially on the mitral valve and pulmonary venous Doppler tracings or tissue Doppler evaluation. The right ventricular particular shape and anatomical position does not permit to use the same parameters for measuring systolic function as is used for the LV. Tricuspid annular plane systolic excursion (TAPSE) and S' velocity on tissue Doppler imaging are more often used for quantitative assessment of right ventricle systolic function. Several parameters proposed to assess right ventricle systolic function such as fractional area change, 3D echocardiography, speckle tracking, and strain rate are being researched and normal values for children are being established. Diastolic function of right ventricle is evaluated by tricuspid valve and hepatic venous Doppler tracings or on tissue Doppler evaluation. The normal values for children are pretty similar to adults while normal values for the neonates, especially preterm infants, may differ significantly from adult population. The normal values for most of the parameters used to assess cardiac function in term neonates and children have now been established.

[Kawasaki disease: an update]. / Maladie de Kawasaki : mise à jour.

The cause of Kawasaki disease (KD) is still unknown, but an infectious origin and genetic susceptibility have been suggested. The American Heart Association has changed the guidelines for diagnosis and treatment of KD in 2017. One goal is to better identify patients most at risk, particularly young children with « incomplete ¼ KD. In case of intravenous immunoglobulin resistance, alternative treatments to the traditional use of corticosteroids, such as TNF-alpha inhibitors have been proposed. For all patients with coronary aneurisms, regular assessment of myocardial perfusion is recommended, either with stress echocardiography, MRI, scintigraphy or PET-scan.

Bien que la cause de la maladie de Kawasaki (MK) reste à ce jour inconnue, les hypothèses actuelles suggèrent une origine infectieuse ainsi qu'une susceptibilité génétique. Les recommandations pour le diagnostic et la prise en charge de la MK ont été modifiées en 2017 par l'American Heart Association. Un des buts est de mieux identifier les patients à risque, en particulier les jeunes enfants avec une MK « incomplète ¼. En cas de résistance au traitement par immunoglobulines intraveineuses, des alternatives thérapeutiques aux corticostéroïdes utilisés traditionnellement sont proposées, incluant les inhibiteurs du TNFα. Chez tout patient avec des anévrismes coronariens, il est conseillé d'avoir une évaluation régulière de la perfusion myocardique, au moyen d'une échocardiographie, d'une IRM ou d'une scintigraphie de stress, ou d'un PET-scan.