Serum calcium normal range in 1000 term newborns.

INTRODUCTION: Serum calcium rapidly declines at birth because of the sudden interruption of the maternal-fetal calcium influx. Several factors are known to influence serum calcium in the first days of life, including circulating concentrations of maternal vitamin D. Objective was to establish the normal range variations of neonatal serum calcium according to the French current vitamin D supplementation during pregnancy, i.e. 100,000 IU of cholecalciferol during the third trimester. METHODS: We included in our prospective cohort study 1002 mother-newborn dyads from, with recruitments from April 2012 to July 2014 in France, in two recruiting centers located in Paris neighborhoods. RESULTS: Total serum calcium at 3 days of life in neonates varied from 2.06 to 2.73 mmol/L [2.5 and 97.5 percentiles], with a mean of 2.45 mmol/L. Serum calcium was similar between babies born from vitamin D supplemented mothers and those born from the non-supplemented ones. Univariate and multivariable analyses demonstrated the importance of maternal and cord blood 25(OH)D concentrations for newborn serum calcium maintenance. CONCLUSION: We established that the expected serum calcium in neonates ranges between 2.06 and 2.73 mmol/L which is significantly wider than the adult range. This finding should help physicians in the diagnosis of hypo- or hypercalcemia. In addition, our study supports the importance of vitamin D supplementation and 25(OH)D status for neonatal serum calcium maintenance.

Medical child abuse: Medical history and red flags in French adolescents.

BACKGROUND: Medical child abuse (MCA; or Munchausen syndrome by proxy) is a severe form of adult and medical maltreatment of children. Currently, few data on MCA in adolescents exist. OBJECTIVE: To describe the clinical characteristics and medical history of children and adolescents aged 10 to 18 years with suspected or confirmed MCA in the pediatric hospital setting. METHODS: We included patients aged 10 to 18 years who were seen in five tertiary care hospitals in the Paris area and identified by physician recall such as suspected MCA between 2015 and 2021. RESULTS: We included 29 adolescents; the mean (SD) age was 12.9 (10.8-15.0) years at suspected diagnosis. Medical wandering was common, with a mean of 23 (12.8-33.2) alleged symptoms and 33 (9.2-56.8) specialized consultations in a mean of six different hospitals. The mean number of emergency visits was 11.8 (0-25.9) and radiologic exams 24.3 (5-43.6). Overall, 62 % (18/29) of the adolescents had an underlying organic pathology. The impact of MCA on quality of life was major, with a high rate of school dropout (96 %). The mean delay to the suspected diagnosis was 5.8 (2.6-9) years, and even when recognized, it was rarely the subject of a social or judiciary report (only 42 % of adolescents). In total, 50 % of the adolescents subsequently exhibited Munchausen syndrome. CONCLUSION: Adolescent MCA is poorly known among the medical profession. Increasing awareness, education and knowledge of risk factors could contribute to better care.

The Severity of Congenital Hypothyroidism With Gland-In-Situ Predicts Molecular Yield by Targeted Next-Generation Sequencing.

INTRODUCTION: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. METHODS: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. RESULTS: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. CONCLUSION: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

Gonadotropin administration to mimic mini-puberty in hypogonadotropic males: pump or injections?

Objective: Newborns with congenital hypogonadotropic hypogonadism (CHH) have an impaired postnatal activation of the gonadotropic axis. Substitutive therapy with recombinant gonadotropins can be proposed to mimic physiological male mini-puberty during the first months of life. The aim of this study was to compare the clinical and biological efficacy of two treatment modalities of gonadotropins administration during mini-puberty in CHH neonates. Design: Multicenter retrospective analytical epidemiological study comparing two treatments, pump vs injection, between 2004 and 2019. Methods: Clinical (penile size, testis size, testicular descent) and biological parameters (serum concentrations of testosterone, anti-Müllerian hormone (AMH) and Inhibin B) were compared between the two groups by multivariate analyses. Results: Thirty-five patients were included. A significantly higher increase in penile length and testosterone level was observed in the injection group compared to the pump group (+0.16 ± 0.02 mm vs +0.10 ± 0.02 mm per day, P = 0.002; and +0.04 ± 0.007 ng/mL vs +0.01 ± 0.008 ng/mL per day, P = 0.001). In both groups, significant increases in penile length and width, testosterone, AMH, and Inhibin B levels were observed, as well as improved testicular descent (odds ratio of not being in a scrotal position at the end of treatment = 0.97 (0.96; 0.99)). Conclusions: Early postnatal administration of recombinant gonadotropins in CHH boys is effective in stimulating penile growth, Sertoli cell proliferation, and testicular descent, with both treatment modalities.

Growth hormone treatment improves final height in children with X-linked hypophosphatemia.

BACKGROUND/AIM: Despite optimal conventional treatment (oral phosphate supplements and active vitamin D analogs), about 40-50% of children with well-controlled X-linked hypophosphatemia (XLH) show linear growth failure, making them less likely to achieve an acceptable final height. Here, we studied the hypothesis that rhGH treatment improves final height in children with XLH and growth failure. METHODS: Two cohorts of children with XLH were included in this retrospective longitudinal analysis: (1) a cohort treated with rhGH for short stature (n = 34) and (2) a cohort not treated with rhGH (n = 29). The mean duration of rhGH treatment was 4.4 ± 2.9 years. We collected the auxological parameters at various time points during follow-up until final height. RESULTS: In rhGH-treated children, 2 years of rhGH therapy was associated with a significant increase in height from - 2.4 ± 0.9 to - 1.5 ± 0.7 SDS (p < 0.001). Their mean height at rhGH discontinuation was - 1.2 ± 0.9 SDS and at final height was - 1.3 ± 0.9 SDS corresponding to 165.5 ± 6.4 cm in boys and 155.5 ± 6.3 cm in girls. Notably, the two groups had similar final heights; i.e., the final height in children not treated with rhGH being - 1.2 ± 1.1 SDS (165.4 ± 6.8 cm in boys and 153.7 ± 7.8 cm in girls), p = 0.7. CONCLUSION: Treatment with rhGH permits to improve final height in children with XLH and growth failure, despite optimal conventional treatment. We propose therefore that rhGH therapy could be considered as an option for short stature in the context of XLH.

People with chronic wounds cared for at home in Belgium: Prevalence and exploration of care integration needs using health care trajectory analysis.

BACKGROUND: Little is known about the prevalence of people with chronic wounds cared for at home and their care integration needs in Belgium. In high-income countries, chronic wounds are associated with ageing processes, chronic diseases and social and financial vulnerability, resulting in multiple needs. To meet these needs, many health care providers (with nurses figuring prominently) are involved. This can lead to fragmented health care trajectories and the need to strengthen care coordination. OBJECTIVES: This study aims to estimate the prevalence of people with chronic wounds cared for at home in Belgium. It also seeks to explore their health care trajectories and the risk of fragmentation of care to inform policy makers, care providers and research. DESIGN: Cross-sectional. SETTING(S): Home care. PARTICIPANTS: Routinely collected data of reimbursed care of 3467 people with a chronic wound cared for at home in 2018. METHODS: We applied a stratification method to our sample based on health care trajectories. First, we constructed individual sequences of care received during the year. Then we summarised the health care events using a K-mers approach. Finally, a multinomial mixture model was used on the previously obtained summary to cluster individuals according to their health care trajectories. Afterwards, other epidemiological, socioeconomic and health care use indicators were calculated for each health care trajectory group. We also estimated the prevalence of people with chronic wounds treated at home. RESULTS: We constructed six health care trajectory groups for two age categories (<65 and ≥65 years) showing different intensity of care use and type of care. In some health care trajectory groups, generalist care was found to be predominant. In others, specialist care appeared more prevalent. Depending on the health care trajectory group, a significant proportion of people had multiple care providers involved (mainly nurses, medical specialists and GPs), and many of them also had multiple transitions between care settings. The prevalence of people with chronic wounds treated at home rises significantly with age: 0.3%, 95%CI (0.2%-0.4%) for people aged under 65, 2.5%, 95%CI (2.3%-2.8%) for people aged 65 and over. CONCLUSION: A significant proportion of people with chronic wounds experienced multiple transitions and met many health care providers. This can lead to complex trajectories and risk of fragmentation. Nurses, who are intensively involved in wound care at home, with the appropriate skills, could play a 'reference' role to promote continuity of care and better coordination. REGISTRATION: Not registered.

Puberty induction with recombinant gonadotropin: What impact on future fertility?

Congenital hypogonadotropic hypogonadism (CHH) is a group of rare diseases characterized by inadequate secretion of the gonadotropins LH (luteinizing hormone) and FSH (follicle stimulating hormone) during the physiological activation periods of the gonadotropic axis. The disease? (anomaly) is present from fetal life and usually persists throughout life. Clinically, hypogonadotropic hypogonadism is associated with neonatal clinical signs (micropenis, cryptorchidism in boys in about half of the cases). The diagnosis is sometimes only evoked in the presence of an absence or arrest of pubertal maturation in the adolescent, which is often poorly tolerated physically and psychologically. Different therapeutic options for pubertal induction have been described, but we lack the necessary larger randomized trials to define the best approaches for both sexes. Historically, congenital hypogonadotropic hypogonadism diagnosed at puberty is treated with testosterone injections. These injections allow the development of secondary sexual characteristics, without an increase in testicular volume in severe forms (FSH deficiency), and a pubertal statural peak. During the last twenty years, studies have underlined the beneficial role of recombinant gonadotropins to induce puberty in this population for future fertility. This is what we will develop.

Comparative analysis of the health status of the population in six health zones in South Kivu: a cross-sectional population study using the WHODAS.

BACKGROUND: The eastern Democratic Republic of Congo (DRC) has experienced decades-long armed conflicts which have had a negative impact on population's health. Most research in public health explores measures that focus on a specific health problem rather than overall population health status. The aim of this study was to assess the health status of the population and its predictors in conflict settings of South Kivu province, using the World Health Organization Disability Assessment Schedule (WHODAS). METHODS: Between May and June 2019, we conducted a community-based cross-sectional survey among 1440 adults in six health zones (HZ), classified according to their level of armed conflict intensity and chronicity in four types (accessible and stable, remote and stable, intermediate and unstable). The data were collected by a questionnaire including socio-demographic data and the WHODAS 2.0 tool with 12 items. The main variable of the study was the WHODAS summary score measuring individual's health status and synthesize in six domains of disability (household, cognitive, mobility, self-care, social and society). Univariate analysis, correlation and comparison tests as well as hierarchical multiple linear regression were performed. RESULTS: The median WHODAS score in the accessible and stable (AS), remote and stable (RS), intermediate (I) and unstable (U) HZ was 6.3 (0-28.6); 25 (6.3-41.7); 22.9 (12.5-33.3) and 39.6 (22.9-54.2), respectively. Four of the six WHODAS domain scores (household, cognitive, mobility and society) were the most altered in the UHZs. The RSHZ and IHZ had statistically comparable global WHODAS scores. The stable HZs (accessible and remote) had statistically lower scores than the UHZ on all items. In regression analysis, the factors significantly associated with an overall poor health status (or higher WHODAS score) were advanced age, being woman, being membership of an association; being divorced, separated or widower and living in an unstable HZ. CONCLUSIONS: Armed conflicts have a significantly negative impact on people's perceived health, particularly in crisis health zones. In this area, we must accentuate actions aiming to strengthen people's psychosocial well-being.

Magnetic resonance imaging is a valuable tool to evaluate the therapeutic efficacy of burosumab in children with X-linked hypophosphatemia.

PURPOSE: To examine the MRI diagnostic performance in the assessment of therapeutic response to burosumab in children with X-linked hypophosphatemia (XLH). DESIGN: Prospective longitudinal open cohort. PATIENTS: Seventeen children with XLH, average age of 10.2 ± 2.7 years, had a knee MRI at baseline and after 1 year of burosumab. INTERVENTION: Children received burosumab at an average dose of 1.4 ± 0.5 mg/kg during 1 year for the treatment of severe rickets (the target serum phosphate ≥ 1.2 mmol/L (≥3.7 mg/dL). The primary endpoint was the change from baseline to 12 months in rachitic lesions on knee MRI. Secondary endpoints were changes in biochemical parameters of phosphate and alkaline phosphatase (ALP). RESULTS: One year of treatment with burosumab significantly reduced radiological disease activity on knee MRI (by 44 ± 29% in the transverse extent of widening) which was accompanied by a significant reduction in biochemical activity, namely in serum ALP activity, by 28 ± 17%. Additionally, MRI parameters after 1 year of treatment with burosumab (the maximum width of medial physis at 12 months and the change from baseline in the maximum width of lateral physis) were associated with ALP activity at 12 months. CONCLUSION: We suggest that MRI is a valuable and quantitative tool to evaluate the therapeutic response to burosumab. MRI could be an excellent alternative to standard bone radiographs for evaluation of the rachitic lesions in a clinical setting avoiding repeated exposition to ionizing radiation.

Determinants of Final Height in Patients Born Small for Gestational Age Treated with Recombinant Growth Hormone.

INTRODUCTION: About 8% of children born small for gestational age (SGA) do not reach a final height within the normal range. Recombinant human growth hormone (rhGH) has been shown to be effective in increasing the final height in children born SGA. Our objective was to identify predictive factors of final height in children born SGA treated with rhGH. MATERIALS AND METHODS: In this retrospective study, conducted in a tertiary pediatric endocrinology referral center, we recruited all patients born SGA (defined as birth length or weight <10th percentile) treated with rhGH for more than 12 months for whom final height data were available. Some patients had received gonadotropin-releasing hormone (GnRH) analog therapy. RESULTS: We included 252 patients with an average birth length of -2.0 ± 0.7 SD and birth weight of -1.7 ± 1.0 SD. After 4.6 ± 2.8 years of rhGH treatment, their height increased from -2.2 ± 0.9 SD to -1.5 ± 0.9 SD. In multivariate analysis, we identified 8 factors that predict 46% of the final height, namely, cause of SGA (p < 0.0001), GnRH analog therapy >2 years (p = 0.006), birth length (p < 0.02), height at the start of rhGH (p < 0.0001), IGF-1 level at the start of rhGH (p = 0.0002), growth velocity during the 1st year of treatment (p = 0.0002), and age and height at the onset of puberty (p < 0.0001, p = 0.0007, respectively). CONCLUSION: In this large cohort of SGA patients who had reached their final height, we were able to confirm that growth hormone increases final height in short SGA children. In addition, we identified several factors associated with a better response to growth hormone treatment.

Increased prevalence of overweight and obesity in children with X-linked hypophosphatemia.

BACKGROUND/AIM: X-linked hypophosphatemia (XLH) is a rare disease characterized by low phosphate levels. Scientific evidence points to a link between hypophosphatemia and obesity in general population. The aim of our longitudinal observational study was to investigate the prevalence of obesity and associated factors in a large cohort of children with XLH. PATIENTS/METHODS: We studied 172 XLH-children 5-20 years of age (113 girls/59 boys). Anthropometric parameters (weight, height, and BMI) were collected at birth and during follow-up at mean ages of 5.3, 8.2, 11.3, and 15.9 years (groups 1, 2, 3, and 4, respectively). In each group, subjects were classified based on International Obesity Taskforce (IOTF) cut off values of BMI for age and sex as overweight or obese (IOTF 25-30 or ≥30 kg/m2, respectively). RESULTS: In each age-group, almost 1/3 of XLH-patients were classified as overweight or obese (29.4, 28.7, 27.5, and 36.7% in groups 1, 2, 3, and 4, respectively). Children without a XLH-family history had higher BMI-IOTF at every point of follow-up, compared to those with positive XLH-family history. Similarly, higher BMI-IOTF was significantly associated with treatment duration (23.3 ± 4.4 vs 23.8 ± 3.8 vs 25.2 ± 4.5 kg/m2, for subjects with treatment duration of <5, 5-10 and >10 years, respectively, P for trend = 0.025). Multiple regression analysis confirmed an association of treatment duration and lack of XLH-family history with higher BMI-IOTF. CONCLUSION: One out of three of XLH-children have phenotypically unfavourable metabolic profile expressed as increased prevalence of overweight or obesity in comparison to general population. Both the lack of XLH family history and the duration of treatment increase the risk of higher BMI-IOTF. BMI should be carefully monitored in children, and later in adults, with XLH.

Patients' perceptions of continuity of care across primary care level and emergency departments in Belgium: cross-sectional survey.

OBJECTIVES: To assess patients' perceptions of continuity of care (COC) across primary care level and emergency departments (EDs) and to identify contextual and individual factors that influence this perception. DESIGN: Cross-sectional multicentre survey. SETTING: Five EDs in Brussels and Wallonia. PARTICIPANTS: 501 adult patients referred to the ED by their primary care physician (PCP). Patients with cognitive impairment or in critical condition were excluded. RESULTS: Patients perceived high levels of the three types of COC. On an individual level, older patients showed a perception of higher levels of continuity. Lower levels of informational and management continuity were observed among patients suffering from chronic diseases and patients with a high level of education. Patients also perceived a redundancy of medical exams, in parallel to a high degree of accessibility between care levels. On an organisational level, three structural factors were identified as barriers to COC, namely, ED workload, suboptimal sharing information system and the current fee-for-service payment system that encourages competition and hinders coordination between actors. CONCLUSION: Belgian healthcare services seem satisfying for patients and easily accessible. However, efforts need to be directed towards improving their efficiency. A stronger primary care level is also needed to benefit the healthcare system by reducing overuse of emergency services. On the individual level, a more enhanced patient-centred approach could be beneficial in improving patients experience of care.

Evaluating case management as a complex intervention: Lessons for the future.

The methodological challenges to effectiveness evaluation of complex interventions has been widely discussed. Bottom-up case management for frail older person was implemented in Belgium, and indeed, it was evaluated as a complex intervention. This paper presents the methodological approach we developed to respond to four main methodological challenges regarding the evaluation of case management: (1) the standardization of the interventions, (2) stratification of the frail older population that was used to test various modalities of case management with different risks groups, (3) the building of a control group, and (4) the use of multiple outcomes in evaluating case management. To address these challenges, we developed a mixed-methods approach that (1) used multiple embedded case studies to classify case management types according to their characteristics and implementation conditions; and (2) compared subgroups of beneficiaries with specific needs (defined by Principal Component Analysis prior to cluster analysis) and a control group receiving 'usual care', to evaluate the effectiveness of case management. The beneficiaries' subgroups were matched using propensity scores and compared using generalized pairwise comparison and the hurdle model with the control group. Our results suggest that the impact of case management on patient health and the services used varies according to specific needs and categories of case management. However, these equivocal results question our methodological approach. We suggest to reconsider the evaluation approach by moving away from a viewing case management as an intervention. Rather, it should be considered as a process of interconnected actions taking place within a complex system.

Evaluation of bottom-up interventions targeting community-dwelling frail older people in Belgium: methodological challenges and lessons for future comparative effectiveness studies.

BACKGROUND: Optimizing the organization of care for community-dwelling frail older people is an important issue in many Western countries. In Belgium, a series of complex, innovative, bottom-up interventions was recently designed and implemented to help frail older people live at home longer. As the effectiveness of these interventions may vary between different population groups according to their long-term care needs, they must be evaluated by comparison with a control group that has similar needs. METHODS: The goal was to identify target groups for these interventions and to establish control groups with similar needs and to explore, per group, the extent to which the utilization of long-term care is matched to needs. We merged two databases: a clinical prospective database and the routine administrative database for healthcare reimbursements. Through Principal Component Analysis followed by Clustering, the intervention group was first stratified into disability profiles. Per profile, comparable control groups for clinical variables were established, based on propensity scores. Using chi-squared tests and logistic regression analysis, long-term care utilization at baseline was then compared per profile and group studied. RESULTS: Stratification highlighted five disability profiles: people with low-level limitations; people with limitations in instrumental activities of daily life and low-level of cognitive impairment; people with functional limitations; people with functional and cognitive impairments; and people with functional, cognitive, and behavioral problems. These profiles made it possible to identify long-term care needs. For instance, at baseline, those who needed more assistance with hygiene tasks also received more personal nursing care (P < 0.05). However, there were some important discrepancies between the need for long-term care and its utilization: while 21% of patients who were totally dependent for hygiene tasks received no personal nursing care, personal nursing care was received by 33% of patients who could perform hygiene tasks. CONCLUSIONS: The disability profiles provide information on long-term care needs but not on the extent to which those needs are met. To assess the effectiveness of interventions, controls at baseline should have similar disability profiles and comparable long-term care utilization. To allow for large comparative effectiveness studies, these dimensions should ideally be available in routine databases.

X-linked hypophosphatemia: Management and treatment prospects.

X-linked hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. Treatment options include active vitamin D analogs and phosphate supplementation to correct the 1.25(OH)2 vitamin D deficiency and to compensate for the renal phosphate wasting, respectively. The recently introduced FGF23 antagonist burosumab is designed to restore renal phosphate reabsorption by the proximal tubule and to stimulate endogenous calcitriol production. In Europe, burosumab is licensed for use in pediatric patients older than 1 year who have XLH. This review discusses the diagnosis and treatment of XLH and describes the indications of the various available treatments.

A new look at population health through the lenses of cognitive, functional and social disability clustering in eastern DR Congo: a community-based cross-sectional study.

BACKGROUND: The importance of viewing health from a broader perspective than the mere presence or absence of disease is critical at primary healthcare level. However, there is scanty evidence-based stratification of population health using other criteria than morbidity-related indicators in developing countries. We propose a novel stratification of population health based on cognitive, functional and social disability and its covariates at primary healthcare level in DR Congo. METHOD: We conducted a community-based cross-sectional study in adults with diabetes or hypertension, mother-infant pairs with child malnutrition, their informal caregivers and randomly selected neighbours in rural and sub-urban health zones in South-Kivu Province, DR Congo. We used the WHO Disability Assessment Schedule 2.0 (WHODAS) to measure functional, cognitive and social disability. The study outcome was health status clustering derived from a principal component analysis with hierarchical clustering around the WHODAS domains scores. We calculated adjusted odds ratios (AOR) using mixed-effects ordinal logistic regression. RESULTS: Of the 1609 respondents, 1266 had WHODAS data and an average age of 48.3 (SD: 18.7) years. Three hierarchical clusters were identified: 9.2% of the respondents were in cluster 3 of high dependency, 21.1% in cluster 2 of moderate dependency and 69.7% in cluster 1 of minor dependency. Associated factors with higher disability clustering were being a patient compared to being a neighbour (AOR: 3.44; 95% CI: 1.93-6.15), residency in rural Walungu health zone compared to semi-urban Bagira health zone (4.67; 2.07-10.58), female (2.1; 1.25-2.94), older (1.05; 1.04-1.07), poorest (2.60; 1.22-5.56), having had an acute illness 30 days prior to the interview (2.11; 1.24-3.58), and presenting with either diabetes or hypertension (2.73; 1.64-4.53) or both (6.37; 2.67-15.17). Factors associated with lower disability clustering were being informally employed (0.36; 0.17-0.78) or a petty trader/farmer (0.44; 0.22-0.85). CONCLUSION: Health clustering derived from WHODAS domains has the potential to suitably classify individuals based on the level of health needs and dependency. It may be a powerful lever for targeting appropriate healthcare service provision and setting priorities based on vulnerability rather than solely presence of disease.

Graves' disease in children.

R1 The diagnosis of Graves' disease in children is based on detecting a suppression of serum TSH concentrations and the presence of anti-TSH receptor antibodies. 1/+++. R2 Thyroid ultrasound is unnecessary for diagnosis, but can be useful for assessing the size and homogeneity of the goiter. 2/+. R3. Thyroid scintigraphy is not required for the diagnosis of Graves' disease. 1/+++. R4. The measurement of T4L and T3L levels is not necessary for the diagnosis of Graves' disease in children but can be useful for the management and assessment of prognosis. 1/++. R5. In the absence of TSH receptor autoantibodies, the possibility of genetically inherited hyperthyroidism must be considered. 1/++. R6. Drug therapy is the primary line of treatment for children and consists of imidazole, carbimazole or thiamazole, with an initial dosage of 0.4 to 0.8mg/kg/day (0.3 to 0.6mg/kg/day for thiamazole) depending on the initial severity, up to maximum of 30mg. 1/++. R7. Propylthiouracil is contraindicated for children with Grave's disease. 1/+++. R8. Before starting treatment, it may be useful to perform a CBC in order to assess the degree of neutropenia caused by hyperthyroidism. It is not necessary to perform systematic CBCs during follow-up. 2/+. R9. An emergency CBC should be performed if symptoms include fever or angina. If neutrophil counts are <1000/mm3, synthetic antithyroid therapy should be discontinued or decreased and may be permanently contraindicated in severe (<500) and persistent neutropenia. Otherwise treatment may be resumed. 1/++. R10. Transaminases levels should be measured before initiating treatment. Systematic monitoring of liver function is not consensually validated. 2/+. R11. In cases of jaundice, digestive disorders or pruritus, measuring liver enzymes (AST, ALT), total and conjugated bilirubin and alkaline phosphatases is indicated. 1/++. R12. Patients and parents should be informed of the possible side effects of antithyroid agents. 1/+. R13. Therapeutic education of parents and children is important in ensuring the best possible treatment compliance. 2/++. R14. Given the specificities involved in the treatment of Graves' disease in children, medical care should be provided by a specialist accustomed to treating endocrinopathies in pediatric patients. 2/+. R15. Depending on patient age, the severity of the disease at diagnosis and the persistence of anti-TSH receptor antibodies, the initial course of treatment must take place over an extended period of 3 to 6 years. R16.The anticipated success rates of medical treatment (50% of patients in remission following several years of treatment) should be explained to the family and the child. The possibility that radical treatment may be required in case of failure or intolerance of medical treatment should also be discussed. 1/++. R17.In females with Graves' disease, it is important to explain that they must undergo an assessment by an endocrinologist before planning future pregnancies, from the start of pregnancy and during the course of pregnancy. This is true in all female patients, even those in remission after medical treatment, or those who have undergone radical treatment. R18.Indications for a radical treatment can arise in cases of: 1/+: contraindication to antithyroid agents; poorly controlled hyperthyroidism due to lack of compliance; relapse despite prolonged medical treatment; a request made by the family and child for personal reasons. R19.Surgery is the radical method of treatment used in children under 5 years of age, or in cases of very large, nodular, or compressive goiters. 2/++. R20. The surgeon's experience in dealing with thyroidectomies in children is likely to be the most significant determining factor in limiting the morbidity of the procedure (alongside any collaboration between a pediatric surgeon and an adult surgeon). 1/++. R21 When radical treatment is indicated, I-131 treatment may be discussed after 5 years (but more often after puberty), if the goiter is not too large. Experience from monitoring Graves' disease in North American children is reassuring. 1/++.

Experimental Warming Differentially Influences the Vulnerability of Phototrophic and Heterotrophic Periphytic Communities to Copper Toxicity.

Aquatic ecosystems are generally subjected to multiple perturbations due to simultaneous or successive combinations of various natural and anthropogenic environmental pressures. To better assess and predict the resulting ecological consequences, increasing attention should be given to the accumulation of stresses on freshwater ecosystems and its effects on the vulnerability of aquatic organisms, including microbial communities, which play crucial functional roles. Here we used a microcosm study to assess the influence of an experimental warming on the vulnerability of phototrophic and heterotrophic periphytic communities to acute and chronic copper (Cu) toxicity. Natural periphytic communities were submitted for 4 weeks to three different temperatures (18, 23, and 28°C) in microcosms contaminated (at about 15 µg L-1) or not with Cu. The vulnerability of both phototrophic and heterotrophic microbial communities to subsequent acute Cu stress was then assessed by measuring their levels of sensitivity to Cu from bioassays targeting phototrophic (photosynthetic activity) and heterotrophic (ß-glucosidase and leucine aminopeptidase extracellular enzymatic activities) microbial functions. We postulated that both the increase in temperature and the chronic Cu exposure would modify microbial community structure, thus leading to changes in the capacity of phototrophic and heterotrophic communities to tolerate subsequent acute exposure to Cu. Our results demonstrated that the influence of temperature on the vulnerability of phototrophic and heterotrophic microbial communities to Cu toxicity can vary greatly according to function studied. These findings emphasize the importance of considering different functional compartments and different functional descriptors to better assess the vulnerability of periphyton to multiple stresses and predict the risks induced by multiple stressors for ecosystem balance and functioning.

15q24.1 BP4-BP1 microdeletion unmasking paternally inherited functional polymorphisms combined with distal 15q24.2q24.3 duplication in a patient with epilepsy, psychomotor delay, overweight, ventricular arrhythmia.

15q24 microdeletion and microduplication syndromes are genetic disorders caused by non-allelic homologous recombination between low-copy repeats (LCRs) in the 15q24 chromosome region. Individuals with 15q24 microdeletion and microduplication syndromes share a common 1.2 Mb critical interval, spanning from LCR15q24B to LCR15q24C. Patients with 15q24 microdeletion syndrome exhibit distinct dysmorphic features, microcephaly, variable developmental delay, multiples congenital anomalies while individuals with reciprocal 15q24 microduplication syndrome show mild developmental delay, facial dysmorphism associated with skeletal and genital abnormalities. We report the first case of a 10 year-old girl presenting mild developmental delay, psychomotor retardation, epilepsy, ventricular arrhythmia, overweight and idiopathic central precocious puberty. 180K array-CGH analysis identified a 1.38 Mb heterozygous interstitial 15q24.1 BP4-BP1 microdeletion including HCN4 combined with a concomitant 2.6 Mb heterozygous distal 15q24.2q24.3 microduplication. FISH analysis showed that both deletion and duplication occurred de novo in the proband. Of note, both copy number imbalances did not involve the 1.2 Mb minimal deletion/duplication critical interval of the 15q24.1q24.2 chromosome region (74.3-75.5 Mb). Sequencing of candidate genes for epilepsy and obesity showed that the proband was hemizygous for paternal A-at risk allele of BBS4 rs7178130 and NPTN rs7171755 predisposing to obesity, epilepsy and intellectual deficits. Our study highlights the complex interaction of functional polymorphisms and/or genetic variants leading to variable clinical manifestations in patients with submicroscopic chromosomal aberrations.

Lower incidence of fracture after IV bisphosphonates in girls with Rett syndrome and severe bone fragility.

BACKGROUND: Classic Rett Syndrome (RS) is a disabling condition mainly caused by MECP2 mutations. Girls with RS are at risk of developing bone fragility and fractures at a young age which results in pain and may seriously impair quality of life. OBJECTIVE: To retrospectively assess the safety and efficacy of IV bisphosphonates on fracture, bone mineral density (BMD) and bone markers in RS girls with bone fragility. METHODS: RS girls received either IV pamidronate (n = 19) or IV zoledronate (n = 1) for 2 years. RESULTS: Of 20 patients studied (age: 12.5 years [6; 39]), 14 were non-ambulatory. The incidence of fracture decreased from 37 fractures in 20 patients, to 1 fracture during or after treatment (follow-up: 3.1 years [1.5; 5]). The spine BMD Z-score improved from -3.2 [-5.6; -0.1] to -2.2 [-3.8; 0.0], p = 0.0006. Most parents reported decreases in chronic pain and 2 patients started to walk. Urinary calcium excretion decreased from 0.7 [0.18; 1.5] to 0.2 [0.03; 0.67] mM/mM of creatinine (p = 0.0001). Pamidronate was well tolerated. CONCLUSION: RS girls should be screened for impaired bone mineralization and preventive measures should be taken. In girls experiencing fractures, IV bisphosphonates constitute a beneficial adjuvant treatment to diminish the risk of fracture and restore bone density.