Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API)

Background: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. / Methods: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. / Results: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. / Conclusion: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe

Moderate Weight Reduction in an Outpatient Obesity Intervention Program Significantly Reduces Insulin Resistance and Risk Factors for Cardiovascular Disease in Severely Obese Adolescents

Background. Metabolic risk factors like insulin resistance and dyslipidemia are frequently observed in severly obese children. We investigated the hypothesis that moderate weight reduction by a low-threshold intervention is already able to reduce insulin resistance and cardiovascular risk factors in severely obese children. Methods. A group of 58 severely obese children and adolescents between 8 and 17 years participating in a six-month-long outpatient program was studied before and after treatment. The program included behavioral treatment, dietary education and specific physical training. Metabolic parameters were measured in the fasting state, insulin resistance was evaluated in an oral glucose tolerance test. Results. Mean standard deviation score of the body mass index (SDS-BMI) in the study group dropped significantly from +2.5 ± 0.5 to 2.3 ± 0.6 (P<0.0001) after participation in the program. A significant decrease was observed in HOMA (6.3 ± 4.2 versus 4.9 ± 2.4, P<0.03, and in peak insulin levels (232.7 ± 132.4 versus 179.2 ± 73.3 μU/mL, P<0.006). Significant reductions were also observed in mean levels of hemoglobin A1c, total cholesterol and LDL cholesterol. Conclusions. These data demonstrate that already moderate weight reduction is able to decrease insulin resistance and dyslipidemia in severely obese children and adolescents

Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut

INTRODUCTION Long-term outcome is postulated to be different in isolated methylmalonic aciduria caused by mutations in the MMAA gene (cblA type) compared with methylmalonyl-CoA mutase deficiency (mut), but case definition was previously difficult. METHOD Cross-sectional analysis of data from the European Registry and Network for Intoxication type Metabolic Diseases (Chafea no. December 1, 2010). RESULTS Data from 28 cblA and 95 mut patients in most cases confirmed by mutation analysis (including 4 new mutations for cblA and 19 new mutations for mut). Metabolic crisis is the predominant symptom leading to diagnosis in both groups. Biochemical disturbances during the first crisis were similar in both groups, as well as the age at diagnosis. Z scores of body height and body weight were similar in both groups at birth, but were significantly lower in the mut group at the time of last visit. Glomerular filtration rate was significantly higher in cblA; and as a consequence, chronic renal failure and related complications were significantly less frequent and renal function could be preserved even in older patients. Neurological complications were predominantly found in the mut subgroup. Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA. 27/28 cblA patients were reported to be responsive to cobalamin, only 86% of cblA patients were treated with i.m. hydroxocobalamin. In total, 73% of cblA and 98% of mut patients followed a calculated diet with amino acid supplements in 27% (cblA) and 69% (mut). During the study interval, six patients from the mut group died, while all cblA patients survived. CONCLUSION Although similar at first, cblA patients respond to hydroxocobalamin treatment, subsequently show significantly lower levels of MMA and a milder course than mut patients

Newborn screening programmes in Europe, arguments and efforts regarding harmonisation: Focus on organic acidurias

Background: The state of newborn screening (NBS) programmes for organic acidurias in Europe was assessed by a web-based questionnaire in the EU programme of Community Action in Public Health 2010/2011 among the – at that time – 27 EU member states, candidate countries, potential candidates and three EFTA countries. Results: Thirty-seven data sets from 39 target countries were analysed. Newborn screening for glutaric aciduria type I (GA-I) was performed in ten, for isovaleric aciduria (IVA) in nine and for methylmalonic aciduria including cblA, cblB, cblC and cblD (MMACBL) as well as for propionic aciduria (PA) in seven countries. Samples were obtained at a median age of 2.5 days and laboratory analysis began at median age of 4.5 days. Positive screening results were mostly confirmed in specialised centres by analysis of organic acids in urine. Confirmation of a positive screening result usually did not start before the second week of life (median ages: 9.5 days [IVA], 9 days [GA-I], 8.5 days [PA, MMACBL]) and was completed early in the third week of life (median ages: 15 days [IVA, PA, MMA], 14.5 days [GA-I]). Treatment was initiated in GA-I and IVA at a median age of 14 days and in MMACBL and PA at a median age of 15 days. Conclusion: NBS for organic acidurias in Europe is variable and less often established than for amino acid disorders. While for GA-I its benefit has already been demonstrated, there is room for debate of NBS for IVA and especially PA and MMACBL

Evaluation of Right Ventricular Function in Patients with Propionic Acidemia—A Cross-Sectional Study

(1) Background: In propionic acidemia (PA), myocardial involvement often leads to progressive cardiac dysfunction of the left ventricle (LV). Cardiomyopathy (CM) is an important contributor to mortality. Although known to be of prognostic value in CM, there are no published data on right ventricular (RV) function in PA patients. (2) Methods: In this cross-sectional single-center study, systolic and diastolic RV function of PA patients was assessed by echocardiography, including frequency, onset, and combinations of echocardiographic parameters, as well as correlations to LV size and function. (3) Results: N = 18 patients were enrolled. Tricuspid annulus S’ was abnormal in 16.7%, RV-longitudinal strain in 11.1%, tricuspid annular plane systolic excursion (TAPSE) in 11.1%, Tricuspid valve (TV) E/e’ in 33.3%, and TV E/A in 16.7%. The most prevalent combinations of pathological parameters were TV E/A + TV E/e’ and TAPSE + TV S’. With age, the probability of developing abnormal RV function increases according to age-dependent normative data. There is a significant correlation between TAPSE and mitral annular plane systolic excursion (MAPSE), and RV/LV-longitudinal strain (p ≤ 0.05). N = 5 individuals died 1.94 years (mean) after cardiac evaluation for this study, and all had abnormal RV functional parameters. (4) Conclusions: Signs of diastolic RV dysfunction can be found in up to one third of individuals, and systolic RV dysfunction in 16.7% of individuals in our cohort. RV function is impaired in PA patients with a poor outcome. RV functional parameters should be used to complement clinical and left ventricular echocardiographic findings

Robotique pour l'apprentissage de gestes médicaux (mise en oeuvre de séquences d'accouchement automatisées)

Le simulateur d accouchement BirthSIM, a été développé pour l enseignement et la formation médicale. Notre travail s inscrit dans le but de définir et mettre en œuvre les différentes procédures d accouchements utiles à l apprentissage des gestes médicaux très importants à maîtriser pour diminuer les risques lors d un accouchement. Après avoir établi le cahier des charges nécessaire pour l automatisation du simulateur, nous avons mis en place un modèle de simulation du système mécatronique constituant le simulateur. Nous présentons un modèle du modulateur de puissance utilisé après avoir effectué une approximation des mesures expérimentales. Ce modèle mathématique nous permet d établir différents modèles de commande nécessaires à la synthèse des méthodologies de commande utilisées pour implanter dix procédures d accouchement. Ces procédures validées expérimentalement font aujourd hui de BirthSIM un simulateur actif et dynamique permettant aujourd hui d assurer l évaluation des praticiens.Our work defines and presents ten new automatic procedures for a mechanical childbirth simulator BirthSIM. BirthSIM is a complete training system for simulating labor during childbirth. This simulator also tests new techniques for obstetric practice. A global simulation model of mecatronic system of BirthSIM has been carried out. An analytical model of proportional valve used has been obtained using characteristic 3D graphs. This model is useful for carrying out the synthesis of linear control laws for feedback control in position, velocity of force tracking according to the desired trajectories. The medical conditions are translated into an automation problem by the synthesis of input trajectories for the electropneumatic system. In this work many control procedures has been proposed: position feedback, force and velocity controls. Different childbirth cases can be simulated by the mecatronic system. The validity of the proposed control method for simulating childbirth modes has been evaluated by means of experiments with an expert obstetrician.VILLEURBANNE-DOC'INSA LYON (692662301) / SudocSudocFranceF