Where are we in our understanding of the association between narcolepsy and one of the 2009 adjuvanted influenza A (H1N1) vaccines?

Evaluating new rare serious vaccine safety signals is difficult and complex work. To further assess the observed increase in narcolepsy cases seen in Europe with the 2009 pandemic H1N1 influenza vaccine, the International Alliance for Biological Standardization (IABS) invited a wide range of experts to a one day meeting in Geneva in October 2015 to present data and to discuss the implications. The presentations covered the following topics: clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaigns; epidemiological studies conducted to assess the risk of narcolepsy, other neurological and immune-related diseases following 2009 pandemic H1N1 influenza vaccine; potential biases influencing the different epidemiological study designs; potential genetic contribution to the development of narcolepsy; potential biological mechanisms for development of narcolepsy in this setting including the role of the virus itself, antigenic differences between the vaccines and differences in AS03-adjuvanted vaccines. The presentations were followed by fulsome roundtable discussions. Members from affected families also attended and made informal comments to round out the day's deliberations. This meeting emphasized the value added in bringing together in a neutral setting a wide range of experts and vaccine producers to discuss such a complex new serious adverse event following immunization.

Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies.

The syntheses of stable isotope labelled internal standards of important CYP-isoform selective probes, like testosterone 1, diclofenac 3, midazolam 5, and dextromethorphan 7, as well as their corresponding hydroxylated metabolites 6ß-hydroxytestosterone 2, 4'-hydroxydiclofenac 4, 1'-hydroxymidazolam 6 and dextrorphan 8 are reported. Microwave-enhanced H/D-exchange reactions applying either acid, base, or homogeneous and heterogeneous transition metal catalysis, or combinations thereof proved to be highly efficient for direct deuterium labelling of the above mentioned probes. Compared to conventional stepwise synthetic approaches, the combination of H/D exchange and biotransformation provides the potential for considerable time- and cost savings, in particular for the synthesis of the stable isotope labelled internal standards of 4'-hydroxydiclofenac 4 and 1'-hydroxymidazolam 6.

[Better medicines for children]. / De meilleurs médicaments pour les enfants.

The European Regulation incenting pharmaceutical companies to develop drugs in children will have substantial consequences for all partners involved. Children and parents will be asked to participate in clinical trials, paediatricians to monitor these investigations, industry to be creative and propose adapted formulations, ethical committees to deliver advices and public health authorities to assist the system in order to bring to a good end a full set of paediatric indications.

Study design in osteoporosis: a European perspective.

The advent of effective agents for the treatment of osteoporosis has led to the view that placebo-controlled trials to test new agents for efficacy are no longer appropriate. Rather, studies of superiority, equivalence, or non-inferiority have been recommended. Such studies require very large sample sizes, and the burden of osteoporotic fracture in a trial setting is substantially increased. Studies of equivalence cannot be unambiguously interpreted because the variance in effect of active comparator agents is too large in osteoporosis. If fracture studies are required by regulatory agencies, there is still a requirement for placebo-controlled studies, although perhaps of shorter duration than demanded at present.

The molar ratio of serum retinol-binding protein (RBP) to transthyretin (TTR) is not useful to assess vitamin A status during infection in hospitalised children.

OBJECTIVE: To assess the usefulness of the molar ratio of serum retinol-binding protein (RBP) to transthyretin (TTR) to determine vitamin A (VA) status during infection. DESIGN: We took advantage of previously collected data during a randomised double-blind, placebo-controlled clinical trial to conduct a secondary analysis of the RBP/TTR ratio and its relationship to infection and VA status. In this clinical trial, children were randomly assigned to one of three groups and received either one single oral high dose of VA (200 000 IU) on the day of admission and subsequently a placebo daily until discharge or daily oral low doses of VA (5000 IU) from admission until discharge or a placebo daily from admission until discharge. SETTING: Lwiro pediatric hospital, Province of South Kivu, Democratic Republic of Congo. SUBJECTS: A total of 900 children aged 0-72 months hospitalised consecutively between March 1994 and March 1996. MAIN OUTCOME MEASURES: RBP/TTR molar ratio after 7 days hospitalisation. RESULTS: After 7 days hospitalisation, molar RBP:TTR ratio (mean+/-s.d.) of infected children (C-reactive proteins>10 mg/l) was 0.67+/-0.31 in the high-dose group (n=81), 0.74+/-0.44 in the low dose group (n=71) and 0.73+/-0.39 in the placebo group (n=81). These values did not differ significantly (one-way ANOVA P=0.472). In patients with baseline serum retinol concentrations<0.70 micromol/l, changes in RBP:TTR ratio between admission and day 7 were not statistically different in the three groups (one-way ANOVA P=0.548). CONCLUSIONS: In this population of malnourished hospitalised children, molar RBP:TTR ratio does not appear to be useful to assess VA status during infection. SPONSORSHIP: Our research was partially supported by a grant from the Fonds de la Recherche Scientifique et Médicale (contract 3.4505.94) and the David and Alice Van Buuren Foundation.

[The food pyramid battle]. / La bataille des pyramides alimentaires.

Two hundred years after Napoleon, nutritionists of the world are fighting against each other in front of the pyramids. In 1995, the USAD (US Agriculture Department) started the battle by publishing "new food recommendations" that should not be confounded with the recommended dietary allowances (RDA). The food choices proposed by the USAD aimed at improving the health of the general population and avoiding chronic diseases. Implicitly these proposals should also meet the RDA. In order to reach its target, the Committee has proposed two pre-requisites: to balance food consumption and energy expenditure and therefore control body weight and to eat among various food items.

[Excessive dietetic restrictions in children]. / Restrictions diététiques abusives chez l'enfant.

Children have specific and increased nutritional requirements in comparison with adults. A rapid growth and an enhanced energy expenditure explain these main differences. Any diet deviation will expose more rapidly to a risk of nutritional deficiency with health consequences. Whenever a diet restriction is required for medical reasons, a particular attention must be paid to the feeding regimen in order to avoid any health problem and mainly growth retardation.

Plasma homocysteine concentration in a Belgian school-age population.

BACKGROUND: Total plasma homocysteine (tHcy) is an independent risk factor for cardiovascular disease in adults. Data for children and adolescents are lacking. OBJECTIVE: The aim of this study was to provide a reference range for tHcy and to explore the relation between tHcy and nutritional indexes in a Belgian pediatric population. DESIGN: tHcy, folate, and vitamin B-12 were measured in 647 healthy children (353 girls and 294 boys) aged 5-19 y. RESULTS: The tHcy distribution was, as in adults, skewed to the right [geometric mean (-1 SD, +1 SD): 7.41 micromol/L (5.51, 9.96)]. Concentrations were lowest in younger children and increased with age. After the tHcy distribution was examined according to age, 3 age ranges were distinguished: 5-9 y [6.21 micromol/L (5.14, 7.50)], 10-14 y [7.09 micromol/L (5.69, 8.84)], and 15-19 y [8.84 micromol/L (6.36, 12.29)]. We observed no significant differences in tHcy values between girls and boys in children aged < 15 y; in postpubertal children, however, concentrations were higher in boys than in girls. In the 3 age groups, folate was inversely correlated with tHcy; the negative relation between tHcy and vitamin B-12 was less strong. Familial cardiovascular disease was more frequent in children who had hyperhomocysteinemia. CONCLUSIONS: These observations suggest that in children, as in adults, genetic, nutritional, and endocrine factors are determinants of the metabolism of homocysteine. The significance of tHcy values in childhood and young adulthood in terms of predicting cardiovascular risk in adulthood should be investigated.

Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children.

The effect of high-dose vitamin A supplementation on recovery from morbidity and on recovery from nosocomial morbidity of hospitalized children has been poorly studied and results are conflicting. The effect of daily, low doses has never been assessed. We investigated the effect of a single high dose and daily, low doses of vitamin A on diarrhea, acute lower respiratory tract infections (ALRIs), and all-cause fevers in 900 hospitalized preschool-age children in the Democratic Republic of Congo in a randomized, double-blind, placebo-controlled clinical trial. The high-dose treatment group received 200,000 IU vitamin A (100,000 IU if aged <12 mo) orally on the day of admission, the low-dose treatment group received 5000 IU vitamin A/d until discharge. Data on all-cause morbidity were collected daily. Mortality rates were not significantly different among the 3 groups. High-dose vitamin A supplementation had no significant effect on the duration of moderate or severe diarrhea nor on the duration and incidence of ALRIs and all-cause fevers. Children in the high-dose group with no edema had an increased risk of severe nosocomial diarrhea (relative risk: 2.42; 95% CI: 1.15, 5.11). Low-dose vitamin A supplementation significantly reduced the incidence of severe diarrhea in severely malnourished children (relative risk: 0.21; 95% CI: 0.07, 0.62) but showed no significant effect on the duration of moderate or severe diarrhea or on the duration and incidence of ALRIs and all-cause fevers. Supplementation with high doses of vitamin A did not reduce morbidity in this population of malnourished and subclinically vitamin A-deficient children; daily, low doses appeared more beneficial for severely malnourished children.

Vitamin A supplementation but not deworming improves growth of malnourished preschool children in eastern Zaire.

A randomized controlled trial was conducted in eastern Zaire to assess the effects of high dose vitamin A supplementation and regular deparasitation on the growth of 358 moderately malnourished preschool children, discharged from the hospital. The treatment groups received either vitamin A (60 mg of oily solution of retinyl palmitate, 30 mg if aged <12 mo) every 6 mo or mebendazole (500 mg) every 3 mo; the control group received no supplementation. Anthropometric data were gathered at baseline and after 6 and 12 mo of follow-up. Serum retinol concentrations were measured at baseline and after 3 mo. The three groups did not differ in sociodemographic indicators, age and sex composition, nutritional status and serum retinol concentrations at baseline. In children who were vitamin A deficient at baseline, adjusted mean weight and mid-upper arm circumference (MUAC) increments were higher in the vitamin A-supplemented group than in the control group [annual increment in weight and MUAC in vitamin A vs. control group: 2.088 vs. 1.179 kg (P = 0.029) and 2.24 vs. 0.95 cm (P = 0.012), respectively], whereas growth increment did not differ between the dewormed group and the control group. In children who were not vitamin A deficient at baseline, growth increment did not differ between the vitamin A-supplemented and control groups, whereas weight gain was lower in the dewormed group than in the control group. Vitamin A-supplemented boys gained more weight and height than control boys, whereas vitamin A-supplemented girls gained less height than control girls. Dewormed boys and girls gained less weight than control boys and girls. Programs to improve vitamin A status by high dose vitamin A supplementation may improve growth of preschool children who are vitamin A deficient, whereas deworming does not.

Effects of cow's milk supplementation on milk output of protein deficient lactating mothers and on their infants' energy and protein status.

A cow's milk supplement providing 500 kcal (2093 kJ) and 18 g of protein a day was given during 2 months to 83 lactating Zairian mothers suffering from protein malnutrition. The mothers' nutritional status improved significantly after 2 months. The initial 24-hour mother's milk output was on average 607 ml (s.d.: 182) and did not change significantly after 2 months (604 ml; s.d.: 178). Initial milk output and change in milk output did not differ according to mothers' nutritional status at inclusion. Breast-fed infants showed a significant improvement of their mean serum albumin concentration while their growth was similar to the mean growth of children of the same age.

Vitamin A deficiency and protein-energy malnutrition in a sample of pre-school age children in the Kivu Province in Zaire.

OBJECTIVE: To assess pre-school age children's vitamin A status in a population where protein-energy malnutrition is endemic and serum retinol binding protein and transtyretin concentrations are low. DESIGN: A cross-sectional study. SETTING: Health district of Katana, South-Kivu, Zaire. SUBJECTS: 415 pre-school age children. METHODS: Three methods were used to assess vitamin A status: ophtalmological examination, retinol serum concentration and Relative Dose Response (RDR) test. RESULTS: The only ophthalmological signs of vitamin A deficiency appeared in two cases of night blindness, which represents a prevalence of 0.7%. Deficient serum retinol concentration (< 0.35 mumol/l) was found in 19.7% of the whole study population and in 10.4% of non-infected children in good nutritional status. RDR test carried out on a reduced sample of 79 subjects was abnormal for 7.6% of the children but showed a low sensitivity when compared with serum retinol concentration. CONCLUSION: This survey suggests that in this population of the South-Kivu Province in Zaire, vitamin A deficiency co-exists with protein-energy malnutrition and is a public health problem even with non-malnourished and non-infected children.

Prognostic indices for mortality of hospitalized children in central Africa.

A hospital-based follow-up study was conducted between 1986 and 1988 at Lwiro (South Kivu Province, Zaire). Of 1,129 children in the study, three of four were severely malnourished, and 17.4% died. This study analyzes the mortality in hospital; its objectives are to evaluate the prognostic power of edema and anthropometric and biologic indicators and to seek indices that perform better. Receiver operating characteristic curves were established for each parameter under study and for each index constructed. Areas under receiver operating characteristic curves were highest for biologic indicators, and simple indices, obtained by counting the number of risk factors present, performed best. In the absence of biologic parameters, the authors suggest classifying children as at risk of dying when they present with edema and/or with arm circumference of less than 115 mm. When biologic measurements are possible, in addition to edema and arm circumference, the authors suggest taking serum albumin and transthyretin into account. For serum albumin and transthyretin, mortality risk is defined in terms of values of less than 16 g/liter and 6.5 mg/dl, respectively. Children will be classified as at risk of dying when they present with at least two of the four risk factors. The resulting diagnostic test has a high sensitivity (91.2%) and positive and negative predictive values of 40.8% and 97.9%, respectively.

Significance of very low retinol levels during severe protein-energy malnutrition.

In developing countries, severe vitamin A deficiency is associated with increased child mortality. In Kivu, Zaïre, child mortality rate is approximately 50 per 1000 per year and protein calorie malnutrition is endemic. To evaluate vitamin A status in this population, we measured plasma retinol levels in 28 severely malnourished hospitalized children (plasma albumin level below 3 g/dl), and in 153 outpatients (mean plasma albumin level: 3.19 +/- 0.7 g/dl) as controls. Sixty percent of inpatients and 37 percent of out-patients had retinol levels below 10 micrograms/dl (P = 0.02) suggesting a high prevalence of severe vitamin A deficiency in this population. We found that plasma retinol levels were correlated with low retinol binding protein plasma levels (r = 0.77). We conclude that although vitamin A deficiency probably exists in this malnourished population, low retinol levels could at least partly be related to decreased levels of its carrier protein.

Biological risk factors for fatal protein energy malnutrition in hospitalized children in Zaire.

Biological markers were used in an attempt to predict mortality in children admitted to the hospital in Kivu, Zaire, for protein energy malnutrition. Data for 39 children who died (16.4%) showed significantly lower levels of albumin (1.61 vs. 2.53 g/dl; p < 0.001), transferrin (82.1 vs. 167.7 mg/dl; p < 0.001), and transthyretin (6.49 vs. 9.87 mg/dl; p < 0.001), but not or retinol-binding protein, than for the 199 survivors. Since albumin and transferrin were correlated, a Cox model was used to see whether albumin or transferrin has a significant predictive value independent of transthyretin. The relative risk predicted by each indicator was of the same order of magnitude, approximately 4. We conclude that specific biological markers help to discriminate among hospitalized subjects at risk and to identify those in need of more intensive nutritional support to prevent early death.

Serum albumin concentration, arm circumference, and oedema and subsequent risk of dying in children in central Africa.

OBJECTIVE: To measure the prognostic value of clinical, anthropometric, and biological indicators of protein energy malnutrition in hospitalised children. DESIGN: Hospital based follow up study from admission to discharge or death of a cohort of children. SETTING-Paediatric hospital in Zaire. SUBJECTS: 1129 children consecutively admitted between August 1986 and October 1988. MAIN OUTCOME MEASURES: Height, weight, arm circumference, skinfold thicknesses, serum albumin concentration, and mortality. RESULTS: Mortality was higher in wasted children and in those with a mid-upper arm circumference < 125 mm, a serum albumin concentration < 16 g/l, and oedema. After multivariate analysis, serum albumin concentration was the best predictor of subsequent risk of dying. Mid-upper arm circumference and oedema, however, still contributed considerably to evaluation of mortality. CONCLUSIONS: In this specific environment of central Africa an isolated clinical sign such as oedema is not enough to detect children with a high risk of dying among those admitted to paediatric wards with severe protein energy malnutrition. Measurement of additional indicators such as arm circumference and serum albumin concentration seems to be of crucial importance.