European survey on national harmonization in clinical research.

BACKGROUND: Clinical trials remain key to the development of evidence-based medical practice. However, they are becoming increasingly complex, mainly in a multinational setting. To address these challenges, the European Union (EU) adopted the Clinical Trial Regulation EU No. 536/2014 (CTR). Once in force, the CTR will lead to more consistent rules and simplification of procedures for conducting clinical trials throughout the EU. Existing harmonization initiatives and "research infrastructures" for clinical trials may facilitate this process. This publication offers a snapshot of the current level of harmonization activities in academic clinical research in Europe. METHODS: A survey was performed among the member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardized questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the harmonization of academic clinical research processes at national level, to facilitate the exchange of expertise and experience among countries, and to identify new fields of action. RESULTS: Most scientific partners already have in place various working groups and harmonization activities at national level. Furthermore, they are involved in and open to sharing their know-how and documents. Since harmonization was mainly a bottom-up approach up until now, the extent and topics dealt with are diverse and there is only little cross-networking and cross-country exchange so far. CONCLUSIONS: Currently, the ECRIN member countries offer a very solid base and collaborative spirit for further aligning processes and exchanging best practices for clinical research in Europe. They can support a smooth implementation of the EU CTR and may act as single contact with consolidated expertise in a country.

Feasibility of high-throughput sequencing in clinical routine cancer care: lessons from the cancer pilot project of the France Genomic Medicine 2025 plan.

BACKGROUND: Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame-that is, compatible with the clinical pathway-is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan. The Multipli study encompasses two innovative trials which will be driven in around 2400 patients suffering from a soft-tissue sarcoma (Multisarc) or a metastatic colorectal carcinoma (Acompli). METHODS: Prior to launching the FGM 2025 cancer pilot study itself, the performance of the Multipli genomic workflow has been evaluated through each step, from the samples collection to the Molecular Tumour Board (MTB) report. Two Multipli-assigned INCa-labelled molecular genetics centres, the CEA-CNRGH sequencing platform and the Institut Bergonié's Bioinformatics Platform were involved in a multicentric study. The duration of each step of the genomic workflow was monitored and bottlenecks were identified. RESULTS: Thirty barriers which could affect the quality of the samples, sequencing results and the duration of each step of the genomic pathway were identified and mastered. The global turnaround time from the sample reception to the MTB report was of 44 calendar days. CONCLUSION: Our results demonstrate the feasibility of tumour genomic analysis by WES/RNASeq within a time frame compatible with the current cancer patient care. Lessons learnt from the Multipli WES/RNASeq Platforms Workflow Study will constitute guidelines for the forthcoming Multipli study and more broadly for the future clinical routine practice in the first two France Genomic Medicine 2025 platforms.

Long-lasting severe immune dysfunction in Ebola virus disease survivors.

Long-term follow up studies from Ebola virus disease (EVD) survivors (EBOV_S) are lacking. Here, we evaluate immune and gene expression profiles in 35 Guinean EBOV_S from the last West African outbreak, a median of 23 months (IQR [18-25]) after discharge from treatment center. Compared with healthy donors, EBOV_S exhibit increases of blood markers of inflammation, intestinal tissue damage, T cell and B cell activation and a depletion of circulating dendritic cells. All survivors have EBOV-specific IgG antibodies and robust and polyfunctional EBOV-specific memory T-cell responses. Deep sequencing of the genes expressed in blood reveals an enrichment in 'inflammation' and 'antiviral' pathways. Integrated analyses identify specific immune markers associated with the persistence of clinical symptoms. This study identifies a set of biological and genetic markers that could be used to define a signature of "chronic Ebola virus disease (CEVD)".

Lassa fever clinical course and setting a standard of care for future randomized trials: A protocol for a cohort study of Lassa-infected patients in Nigeria (LASCOPE).

BACKGROUND: Lassa Fever (LF), is a severe viral disease prevalent in Western Africa. It is classified as a priority disease by the World Health Organization (WHO). Ribavirin is the recommended therapy despite weak evidence of its efficacy. Promising therapeutic agents are becoming available for evaluation in human. Before launching therapeutic trials, we need data on the evolution of the disease under the best possible conditions of care. METHODS: We have initiated a prospective study in Nigeria to better understand the clinical course and prognostic factors of LF while implementing high quality standardized care. Inclusion criteria are: suspected or confirmed LF and informed consent. Participants are followed 60 days from admission and receive free of charge standardized supportive care and biological monitoring, as well as intravenous ribavirin for those with confirmed LF. Data are collected using standardized case report forms (CRF). Primary and secondary outcomes are fatality and severe morbidity, with special focus on acute kidney dysfunction and pregnancy complications. Factors associated with outcomes will be investigated. RESULTS: The cohort is planned for 3 years. Inclusions started in April 2018 at the Federal Medical Center Owo in Ondo State. A second site will open in Nigeria in 2020 and discussions are underway to open a site in Benin. 150 to 200 new participants are expected per year. CONCLUSIONS: This cohort will: provide evidence to standardize LF case management; provide key inputs to design future clinical trials of novel therapeutics; and establish clinical research teams capable of conducting such trials in LF-endemic areas. STUDY REGISTRATION: The LASCOPE study was registered on ClinicalTrial.gov (NCT03655561).

Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.

Enrolling study personnel in Ebola vaccine trials: from guidelines to practice in a non-epidemic context.

BACKGROUND: Enrolling participants in clinical trials can be challenging, especially with respect to prophylactic vaccine trials. The vaccination of study personnel in Ebola vaccine trials during the 2014-2016 epidemic played a crucial role in inspiring trust and facilitating volunteer enrollment. We evaluated the ethical and methodological considerations as they applied to an ongoing phase 2 randomized prophylactic Ebola vaccine trial that enrolled healthy volunteers in Guinea, Liberia, Sierra Leone, and Mali in a non-epidemic context. METHODS: On the assumption that the personnel on site involved in executing the protocol, as well as community mobilizers (not involved in the on-site procedures), might also volunteer to enter the trial, we considered both ethical and methodological considerations to set clear rules that can be shared a priori with these persons. We reviewed the scientific and gray literature to identify relevant references and then conducted an analysis of the ethical and methodological considerations. RESULTS: There are currently no regulations preventing a clinical investigator or site staff from participating in a trial. However, the enrollment of personnel raises the risk of undue influence and challenges the basic ethical principle of voluntary participation. The confidentiality of personal medical information, such as HIV test results, may also be difficult to ensure among personnel. There is a risk of disruption of trial operations due to the potential absence of the personnel for their commitment as trial participants, and there is also a potential for introducing differential behavior of on-site staff as they obtain access to accumulating information during the trial (e.g., the incidence of adverse events). Blinding could be jeopardized, given knowledge of product-specific adverse event profiles and the proximity to unblinded site staff. These aspects were considered more relevant for on-site staff than for community mobilizers, who have limited contact with site staff. CONCLUSION: In a non-epidemic context, ethical and methodological considerations limit the collective benefit of enrolling site staff in a vaccine trial. These considerations do not apply to community mobilizers, whose potential enrollment should be considered as long as they meet the inclusion criteria and they are not exposed to any form of coercion.

Safety and efficacy of the rSh28GST urinary schistosomiasis vaccine: A phase 3 randomized, controlled trial in Senegalese children.

BACKGROUND: Urinary schistosomiasis, the result of infection by Schistosoma haematobium (Sh), remains a major global health concern. A schistosome vaccine could represent a breakthrough in schistosomiasis control strategies, which are presently based on treatment with praziquantel (PZQ). We report the safety and efficacy of the vaccine candidate recombinant 28-kDa glutathione S-transferase of Sh (rSh28GST) designated as Bilhvax, in a phase 3 trial conducted in Senegal. METHODS AND FINDINGS: After clearance of their ongoing schistosomiasis infection with two doses of PZQ, 250 children aged 6-9 years were randomized to receive three subcutaneous injections of either rSh28GST/Alhydrogel (Bilhvax group) or Alhydrogel alone (control group) at week 0 (W0), W4, and W8 and then a booster at W52 (one year after the first injection). PZQ treatment was given at W44, according to previous phase 2 results. The primary endpoint of the analysis was efficacy, evaluated as a delay of recurrence of urinary schistosomiasis, defined by a microhematuria associated with at least one living Sh egg in urine from baseline to W152. During the 152-week follow-up period, there was no difference between study arms in the incidence of serious adverse events. The median follow-up time for subjects without recurrence was 22.9 months for the Bilhvax group and 18.8 months for the control group (log-rank p = 0.27). At W152, 108 children had experienced at least one recurrence in the Bilhvax group versus 112 in the control group. Specific immunoglobulin (Ig)G1, IgG2, and IgG4, but not IgG3 or IgA titers, were increased in the vaccine group. CONCLUSIONS: While Bilhvax was immunogenic and well tolerated by infected children, a sufficient efficacy was not reached. The lack of effect may be the result of several factors, including interference by individual PZQ treatments administered each time a child was found infected, or the chosen vaccine-injection regimen favoring blocking IgG4 rather than protective IgG3 antibodies. These observations contrasting with results obtained in experimental models will help in the design of future trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00870649.

High Prevalence of Polycystic Ovary Syndrome in Type 1 Diabetes Mellitus Adolescents: Is There a Difference Depending on the NIH and Rotterdam Criteria?

BACKGROUND: Polycystic ovary syndrome (PCOS) is more frequently observed in type 1 diabetes mellitus (T1DM) adult women than in nondiabetic women. No such prevalence has yet been studied in adolescent girls with T1DM. AIM: The aim of this study was to evaluate the prevalence of PCOS in adolescent girls with T1DM and to determine the clinical and hormonal features associated with the disorder. METHODS: A cross-sectional study of 53 adolescent girls (gynecological age >2 years) referred for routine evaluation for T1DM was conducted. We diagnosed PCOS using the National Institutes of Health (NIH) and Rotterdam criteria. RESULTS: 26.4 and 47.9% of adolescents had PCOS according to NIH (NIH-PCOS) and Rotterdam (Rotterdam-PCOS) criteria. 66.7% of NIH-PCOS adolescents had a complete phenotype associated with hyperandrogenism, oligomenorrhea, and polycystic ovarian morphology, unlike only 33.3% of the Rotterdam-PCOS adolescents. A family history of type 2 diabetes mellitus (T2DM) was more frequent in PCOS than in non-PCOS girls, whichever criteria were used. Late pubertal development and a T1DM diagnosis close to puberty were factors associated with NIH-PCOS. CONCLUSION: Adolescents with T1DM had a high prevalence of PCOS. More differences between PCOS and non-PCOS patients were found using the NIH criteria, suggesting that clinical characteristics might be more accurate for diagnosing PCOS in girls with T1DM. A family history of T2DM is associated with a high risk of PCOS.

Relationship between salivary/pancreatic amylase and body mass index: a systems biology approach.

BACKGROUND: Salivary (AMY1) and pancreatic (AMY2) amylases hydrolyze starch. Copy number of AMY1A (encoding AMY1) was reported to be higher in populations with a high-starch diet and reduced in obese people. These results based on quantitative PCR have been challenged recently. We aimed to re-assess the relationship between amylase and adiposity using a systems biology approach. METHODS: We assessed the association between plasma enzymatic activity of AMY1 or AMY2, and several metabolic traits in almost 4000 French individuals from D.E.S.I.R. longitudinal study. The effect of the number of copies of AMY1A (encoding AMY1) or AMY2A (encoding AMY2) measured through droplet digital PCR was then analyzed on the same parameters in the same study. A Mendelian randomization analysis was also performed. We subsequently assessed the association between AMY1A copy number and obesity risk in two case-control studies (5000 samples in total). Finally, we assessed the association between body mass index (BMI)-related plasma metabolites and AMY1 or AMY2 activity. RESULTS: We evidenced strong associations between AMY1 or AMY2 activity and lower BMI. However, we found a modest contribution of AMY1A copy number to lower BMI. Mendelian randomization identified a causal negative effect of BMI on AMY1 and AMY2 activities. Yet, we also found a significant negative contribution of AMY1 activity at baseline to the change in BMI during the 9-year follow-up, and a significant contribution of AMY1A copy number to lower obesity risk in children, suggesting a bidirectional relationship between AMY1 activity and adiposity. Metabonomics identified a BMI-independent association between AMY1 activity and lactate, a product of complex carbohydrate fermentation. CONCLUSIONS: These findings provide new insights into the involvement of amylase in adiposity and starch metabolism.

Associations Between Type 2 Diabetes-Related Genetic Scores and Metabolic Traits, in Obese and Normal-Weight Youths.

CONTEXT: Young-onset obesity is strongly associated with the early development of type 2 diabetes (T2D). Genetic risk scores (GRSs) related to T2D might help predicting the early impairment of glucose homeostasis in obese youths. OBJECTIVE: Our objective was to investigate the contributions of four GRSs (associated with: T2D [GRS-T2D], beta-cell function [GRS-ß], insulin resistance [GRS-IR], and body mass index) to the variation of traits derived from oral glucose tolerance test (OGTT) in obese and normal-weight children and young adults. DESIGN: This was a cross-sectional association study. PATIENTS: A total of 1076 obese children/adolescents (age = 11.4 ± 2.8 years) and 1265 normal-weight young volunteers (age = 21.1 ± 4.4 years) of European ancestry were recruited from pediatric obesity clinics and general population, respectively. INTERVENTION: Standard OGTT was the intervention in this study. MAIN OUTCOME MEASURES: Associations between GRSs and OGTT-derived traits including fasting glucose and insulin, insulinogenic index, insulin sensitivity index, disposition index (DI) and associations between GRSs and pre-diabetic conditions were measured. RESULTS: GRS-ß significantly associated with fasting glucose (ß = 0.019; P = 3.5 × 10-4) and DI (ß = -0.031; P = 8.9 × 10-4, last quartile 18% lower than first) in obese children, and nominally associated with fasting glucose (ß = 0.009; P = 0.017) and DI (ß = -0.030; P = 1.1 × 10-3, last quartile 11% lower than first) in normal-weight youths. GRS-T2D showed weaker contribution to fasting glucose and DI compared to GRS-ß, in both obese and normal-weight youths. GRS associated with insulin resistance and GRS associated with body mass index did not associate with any traits. None of the GRSs associated with prediabetes, which affected only 4% of participants overall. CONCLUSION: Single nucleotide polymorphisms identified by genome-wide association studies to influence beta-cell function were associated with fasting glucose and indices of insulin secretion in youths, especially in obese children.

Weight for gestational age and metabolically healthy obesity in adults from the Haguenau cohort.

BACKGROUND: An obesity subphenotype, named 'metabolically healthy obese' (MHO) has been recently defined to characterise a subgroup of obese individuals with less risk for cardiometabolic abnormalities. To date no data are available on participants born with small weight for gestational age (SGA) and the risk of metabolically unhealthy obesity (MUHO). OBJECTIVE: Assess the risk of MUHO in SGA versus appropriate for gestational age (AGA) adult participants. METHODS: 129 young obese individuals (body mass index ≥30 kg/m²) from data of an 8-year follow-up Haguenau cohort (France), were identified out of 1308 participants and were divided into 2 groups: SGA (n=72) and AGA (n=57). Metabolic characteristics were analysed and compared using unpaired t-test. The HOMA-IR index was determined for the population and divided into quartiles. Obese participants within the first 3 quartiles were considered as MHO and those in the fourth quartile as MUHO. Relative risks (RRs) and 95% CI for being MUHO in SGA versus AGA participants were computed. RESULTS: The SGA-obese group had a higher risk of MUHO versus the AGA-obese group: RR=1.27 (95% CI 1.10 to 1.6) independently of age and sex. CONCLUSIONS: In case of obesity, SGA might confer a higher risk of MUHO compared with AGA.

Dietary intake in young adults born small or appropriate for gestational age: data from the Haguenau cohort.

OBJECTIVES: Compare the dietary intake of young adults born small for gestational age (SGA) versus those born appropriate for gestational age (AGA). DESIGN: Cross-sectional analysis. SETTING: Data at the 8-year follow-up Haguenau cohort (France). Data from 229 AGA-born adults and 172 SGA-born adults with available dietary information are presented. METHODS: Dietary intake was based on a food questionnaire including 19 items. The χ(2) test was run to compare intake between SGA-born and AGA-born individuals. An a priori score was calculated based on the adherence to recommendations from the French Nutrition and Health Program and included 8 components with the lowest value indicating a lower adherence to recommendations. The score was then divided into quartiles. Relative risks and 95% CIs, controlling for age and sex in multivariate analysis, were calculated in order to determine the risk of belonging to the first versus the second to the fourth quartiles in SGA-born and AGA-born individuals. RESULTS: Intakes of SGA-born adults indicated that they consumed more meat, sugar and less fish than AGA-born individuals (all p<0.05). Multivariate analyses with adjustment for age and sex showed that the relative risk of belonging to the first quartile versus the other three quartiles did not disclose any significant difference in SGA-born versus AGA-born participants: RR=0.92 (95% CI 0.65 to 1.30). CONCLUSIONS: Aside from the differences found by univariate analyses, no significant differences were obtained in multivariate analyses. Findings suggest that parameters of fetal programming are more associated with the development of metabolic syndrome in adulthood rather than dietary patterns.

Contribution of the low-frequency, loss-of-function p.R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels.

BACKGROUND: We previously reported that the low-frequency, loss-of-function variant p.R270H in FFAR4 encoding the lipid sensor GPR120 was associated with obesity. Gpr120-deficient mice develop obesity and both impaired fasting glucose and glucose intolerance under a high-fat diet. We aimed to assess the contribution of p.R270H to type 2 diabetes (T2D) risk and the variation of glucose-related traits. METHODS: We genotyped p.R270H in 8996 non-diabetic individuals (among whom 4523 had an oral glucose tolerance test (OGTT)) and in a T2D case-control study including 4725 cases and 4339 controls. The regression models were adjusted for age, sex and body mass index (BMI). RESULTS: We found a significant association between p.R270H and increased fasting glucose levels (ß=0.092±0.05 mmol/L; p=4.13×10(-4)). Furthermore, p.R270H nominally contributed to decreased homeostasis model of pancreatic ß-cell function (HOMA-B; ß=-0.090±0.06; p=6.01×10(-3)). Despite a high statistical power, we did not find any significant association between p.R270H and T2D risk or the variation of fasting insulin levels, the homeostasis model of insulin resistance or OGTT-derived indices. CONCLUSIONS: These results suggest that the low-frequency p.R270H variant which inhibits GPR120 activity might influence fasting glucose levels in a normal physiological range. This study does not exclude that other coding mutations in FFAR4 with stronger functional effect than p.R270H may be associated with T2D.

Promoting the place of the allied health professions in clinical research.

Clinical research is of major importance to today's society, as scientific evidence is increasingly demanded as a basis for progress, whether this involves developing new healthcare products, improving clinical practice and care protocols or progress in prevention. Clinical research therefore requires professionals who are both experienced and increasingly well trained. Against this background, allied health professionals are becoming involved more and more, both as team members supporting clinical research projects and as managers or coordinators of projects in their own field. Clinical research activities provide an ideal opportunity for continuing professional development. All of this means that the professional skills of the allied health professions and clinical research support professions must be enhanced, their role promoted in the context of lecturer status and in the longer term, their status recognised by the supervisory authorities.

SGA children with moderate catch-up growth are showing the impaired insulin secretion at the age of 4.

BACKGROUND: Being born small for gestational age (SGA) is a risk factor for later development of type 2 diabetes. The development of glucose tolerance disorders in adults involves insulin resistance and impaired insulin secretion. OBJECTIVE: To evaluate insulin secretion and insulin sensitivity in a 4-yr old cohort of SGA. METHODS: 85 children were prospectively followed from mid-gestation to 4 years of age. Fetal growth velocity (FGV) was measured using ultrasound measurements. Body composition and hormonal profile were measured at birth, 1 and 4 years. RESULTS: 23 SGA babies had lower birth weight compared to 62 AGA (-1.9±0.3 vs. -0.6±0.8 z-score; p<0.0001) and they were thinner at birth (ponderal index 24.8±1.8 vs. 26.3±3.1 kg/m3; p = 0.01 and fat mass 11±2.6 vs. 12.9±3.1%; p = 0.01). No significant differences in other measured metabolic and hormonal parameters were observed between two groups at birth. SGA infants experienced an early catch-up growth in weight (mean gain of 1.1±0.6 SD) during the first year of life. At 4 years, SGA children remain lighter than AGA, but with weight z-score in the normal range (-0.1±1.3 vs. 0.5±1.3 z-score; p = 0.05). No excess of fat mass was observed (19±4.8 vs. 19.7±4.1%; p = 0.45). 120-min plasma glucose was significantly higher (6.2±1.1 vs. 5.6±0.9 mmol/l; p = 0.006) and insulinogenic index was significantly lower (0.28±0.15 vs. 0.40±2.4; p = 0.02) in the SGA group at 4-yrs of life contrasting with a preserved insulin sensitivity (QUICKI 0.47±0.09 vs. 0.43±0.05; p = 0.06). CONCLUSION: SGA children with compensatory catch-up growth in first year of life show mild disturbances of glucose tolerance associated to a lower insulinogenic index at 4-yrs of age suggesting impairment of ß-cell function.

A central role for GRB10 in regulation of islet function in man.

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

Innate small babies are metabolically healthy children.

BACKGROUND: Being born small for gestational age (SGA) is regarded as a risk factor for later metabolic complications. The SGA is defined as a birth weight below -2 SD of the distribution for sex and gestational age. However, the definition of SGA does not distinguish between those born after fetal growth restriction and innate SGA (iSGA). OBJECTIVE: Our objective was to test whether innate SGA infants show any metabolic complications at the age of 2 yr in comparison with infants born appropriate for gestational age (AGA). METHODS: Fifty-eight infants with family SGA risk factors (SGA in a previous pregnancy or among parents, maternal height less than -2 sd for adult height in French women, and small fetal size at second-trimester ultrasound examination) were prospectively followed from midgestation to 2 yr of age. Fetal growth velocity was measured from ultrasound measurements. Body composition and hormonal profile were measured at birth and 1 and 2 yr. RESULTS: Fetal growth velocity was not significantly different between iSGA and AGA (-0.17 ± 0.2 vs. -0.17 ± 0.3 percentiles/d of gestation; P = 0.96). iSGA infants were significantly lighter at birth (-1.7 ± 0.45 vs. 0.46 ± 0.77 SD; P < 0.0001) and at 4 months of age (-0.85 ± 0.88 vs. 0.29 ± 1 SD; P < 0.0001), and they remain so over follow-up (-0.73 ± 1.08 vs. 0.2 ± 1.02 SD; P = 0.0014 at 2 yr). Height z-scores and percent fat time courses followed a similar pattern. No differences in any of the metabolic and hormonal parameters were observed between iSGA and AGA up to 2 yr (insulin at birth, 5.1 ± 6.8 vs. 5.2 ± 4.6 mIU/liter, P = 0.2; at 2 yr, 2 ± 1.6 vs. 2 ± 1.5 mIU/liter, P = 0.66). CONCLUSION: Infants born iSGA do not experience severe fetal growth restriction and do not show any evidence of metabolic risk either at birth or in the first 2 yr of life.

Novel modeling of reference values of cardiovascular risk factors in children aged 7 to 20 years.

BACKGROUND AND OBJECTIVE: Most of the cardiovascular risk factors strongly associated with obesity and overweight vary with age and gender. However, few reference values are available for healthy European children. Our objective was to establish pediatric reference ranges for waist circumference, systolic and diastolic blood pressures, fasting lipid levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), glucose, and insulin. METHODS: A representative sample of 1976 healthy French individuals (1004 female participants and 972 male participants) aged 7 to 20 years was used to obtain age- and gender-specific normal ranges for each of the above-listed cardiovascular risk factors, based on the Royston and Wright method. RESULTS: Mean waist circumference increased with age in both genders and was slightly higher in males than in females. Whereas systolic blood pressure increased gradually with age, with the increase being steeper in males than in females, no gender effect was found for diastolic blood pressure, which was therefore modeled after pooling males and females. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride values varied little with age and gender. Glucose and insulin levels revealed pubertal peaks, which were sharper in females than in males, reflecting the normal insulin resistance during puberty. CONCLUSIONS: These ranges can be used as references for European children to monitor cardiovascular risk factors and to plan interventions and education programs.