Search

COVID-19 limitation strategies have led to widespread school closures around the world. The present study reports children’s mental health and associated factors during the COVID-19 school closure in France in the spring of 2020. We conducted a cross-sectional analysis using data from the SAPRIS project set up during the COVID-19 pandemic in France. Using multinomial logistic regression models, we estimated associations between children’s mental health, children’s health behaviors, schooling, and socioeconomic characteristics of the children’s families. The sample consisted of 5702 children aged 8–9 years, including 50.2% girls. In multivariate logistic regression models, children’s sleeping difficulties were associated with children’s abnormal symptoms of both hyperactivity-inattention (adjusted Odds Ratio (aOR) 2.05; 95% Confidence Interval 1.70–2.47) and emotional symptoms (aOR 5.34; 95% CI 4.16–6.86). Factors specifically associated with abnormal hyperactivity/inattention were: male sex (aOR 2.29; 95% CI 1.90–2.76), access to specialized care prior to the pandemic and its suspension during school closure (aOR 1.51; 95% CI 1.21–1.88), abnormal emotional symptoms (aOR 4.06; 95% CI 3.11–5.29), being unschooled or schooled with assistance before lockdown (aOR 2.13; 95% CI 1.43–3.17), and tutoring with difficulties or absence of a tutor (aOR 3.25; 95% CI 2.64–3.99; aOR 2.47; 95% CI 1.48–4.11, respectively). Factors associated with children’s emotional symptoms were the following: being born pre-term (aOR 1.34; 95% CI 1.03–1.73), COVID-19 cases among household members (aOR 1.72; 95% CI 1.08–2.73), abnormal symptoms of hyperactivity/inattention (aOR 4.18; 95% CI 3.27–5.34) and modest income (aOR 1.45; 95% CI 1.07–1.96; aOR 1.36; 95% CI 1.01–1.84). Multiple characteristics were associated with elevated levels of symptoms of hyperactivity-inattention and emotional symptoms in children during the period of school closure due to COVID-19. Further studies are needed to help policymakers to balance the pros and cons of closing schools, taking into consideration the educational and psychological consequences for children.

International audience; Objective: 25-hydroxyvitamin D (25OHD) deficiency has been associated with sleep disorders in adults. Only three cross-sectional studies were performed in children and showed an association between 25OHD deficiency and both obstructive sleep apnea syndrome and primary snoring. No longitudinal study has been performed in children from the general population. We analyzed the association between cord-blood vitamin D level at birth and night-sleep duration trajectories for children between 2 and 5-6 years old in a non-clinical cohort.Method: We included 264 children from the French EDEN mother-child birth-cohort with both cord-blood 25OHD level determined by radio-immunoassay at birth, and night-sleep trajectories for children between 2 and 5-6 years old obtained by the group-based trajectory modeling method. Associations between 25OHD and sleep trajectories were assessed by multinomial logistic regression adjusted for maternal and child characteristics.Results: The trajectories short sleep (

High cognitive functioning could be a protective factor for school difficulties, behavioral and mood impairments in children with narcolepsy. To investigate this factor, we studied the intellectual abilities of 74 children with narcolepsy (43 boys, 11.7 years old at diagnosis, 91% of cataplexies, 64% obese, 100% HLA positive for DR-DQB1*06:02). All children underwent a one-night polysomnography followed by Multiple Sleep Latency Tests, an evaluation of intelligence quotient (IQ), and filled standardized questionnaires. Thirty-eight percent had high potentialities (HP defined by IQ &gt, 130) and 48% had school difficulties. Using non-parametric tests, we found that HP children reported less difficulties at school and tended to have less impulsivity, conduct, and learning disorders than those without HP. They also tended to be less obese and had less desaturation. Using a multivariate regression analysis, we found an association between the REM sleep percentage and the IQ. REM sleep could be involved in the dynamic changes contributing to the equilibrium of intellectual functioning. This study highlights that despite their frequent school difficulties, narcolepsy per se is unlikely to be a cause of intellectual disability in children. Prompt diagnosis and management of comorbidities such as obesity and obstructive sleep apnea (OSA) could improve cognitive and school performances in these children.

International audience; Sleep occupies a substantial proportion of life. Sleep modifications parallel brain development during childhood. Sex and gender differences have been reported in brain development and many clinical and psychosocial conditions. This narrative review provides insight into the differences between girls and boys in terms of brain maturation and plasticity related to sleep and sleep characteristics (physiology, sleep duration) during development.

International audience; Background: Short sleep duration is associated with concomitant behavioral difficulties, but the longitudinal association between sleep duration and later behavior in early childhood remains unclear. The aim was to study the association between sleep duration trajectories throughout preschool and behavior at age 5-6 years.Participants: 1021 children of the French birth-cohort EDEN were included in this study.Methods: Night-sleep duration trajectories were modeled on the basis of repeated measures collected at age 2, 3 and 5-6 years by parental questionnaires. Behavior was assessed with the Strengths and Difficulties Questionnaire (SDQ), with five subscales measuring conduct problems, emotional symptoms, peer relation problems, antisocial behavior, and hyperactivity-inattention problems. The subscales were dichotomized by the 25th percentile. Multivariable logistic regression, adjusted for baseline behavior, and assessment of multiple confounding factors allowed for studying the independent association between night-sleep duration trajectories from age 2 to 5-6 and behavior at age 5-6.Results: Five distinct sleep-duration trajectories were identified. At age 5-6 years, probability of hyperactivity-inattention problems was increased for boys belonging to the "short sleep" and "medium-low sleep" duration trajectory and girls belonging to the "changing sleep" duration trajectory as compared with children with the medium-high sleep duration trajectory (boys: OR 2.69 [95% CI 1.18-6.16], p = .03 and 1.95 [1.25-3.03], p = .003, and girls: OR 2.79 [1.09- 7.17], p = .03). No associations were observed with the other SDQ subscales.Conclusion: The persistence of short night-sleep durations in preschool years as well as a sudden decrease at age 3 are risk factors of hyperactivity-inattention problems at school start.

This work was conducted in the framework of the French network for Nutrition And Cancer Research (NACRe network), www.inra.fr/nacre.; International audience; Circadian disruption has been classified as probably carcinogenic to humans by the World Health Organization's International Agency for Research on Cancer. The circadian clock is subject to environmental factors, particularly light exposure and food intake rhythms. However, the association between nutritional circadian behaviours and cancer is not well understood. We investigated the longitudinal associations between number of eating episodes, night-time fasting duration, time of first and last eating episodes, as well as nutritional quality of last eating episode, respectively, with breast and prostate cancer risks, the two main cancer locations in women and men respectively. This prospective study included 41,389 day-working adults in the French NutriNet-Santé cohort (2009-2016) who completed at least three 24 h dietary records during the first 2 years of follow-up. Multivariable Cox models were computed. 1,732 first primary incident cancer cases were diagnosed during the follow-up, among which 428 breast and 179 prostate cancers. After adjustment for covariates including sleep duration, late eaters (last eating episode after 9:30 pm) had an increased risk of breast (Hazard ratio [HR] = 1.48 [1.02-2.17], p = 0.03) and prostate (HR = 2.20 [1.28-3.78], p = 0.004) cancers. However, no association was observed between cancer risk and number of eating episodes, night-time fasting duration, time of first eating episode or macronutrient composition of the last eating episode. This large cohort study suggests that circadian perturbations resulting from late time of last food intake may be involved in carcinogenesis at different locations. Beyond nutritional quality of food intake, nutritional circadian regulation should be further investigated in the context of cancer prevention.

Background. Few studies on the relations between sleep quantity and/or quality and cognition were conducted among pre-schoolers from healthy general population. We aimed at identifying, among 3 years old children, early factors associated with intelligence quotient estimated through Weschler Preschool and Primary Scale Intelligence-III test and its indicators: full-scale-, verbal- and performance-intelligence quotients and their sub-scale scores. Methods. We included 194 children from the French birth-cohort AuBE with both available Weschler Preschool and Primary Scale Intelligence-III scores at 3y and sleep data. Information was collected through self-questionnaires at birth, 6, 12, 18 and 24 months. A day/night sleep ratio was calculated. Results. Mean scores were in normal ranges for verbal-, performance- and full-scale-intelligence quotients. In multivariate models, being a $\ge$3 born-child and watching television $\ge$1 hour/day at 24 months were negatively associated with all intelligence quotient scores while collective care arrangement was positively associated. Night waking at 6 and frequent snoring at 18 months were negatively associated with performance intelligence quotient, some subscales and full-scale-intelligence quotient contrary to day/night sleep ratio at 12 months. No association was observed between early sleep characteristics and verbal intelligence quotient. Conclusion. We showed that early features including infant sleep characteristics influence intelligence quotient scores at 3 years old. Some of these may be accessible to prevention.

Infant sleep plays a critical role in his/her normal development. Sleep problems, including sleep onset difficulties (SOD) and night waking (NW), ranges from 20% to 30% in infants and young children and are partially persistent over time up to adulthood. French young children seem to have longer sleep durations and less sleep troubles than their counterparts worldwide. We here aimed at describing infants sleep characteristics (duration/24h (TST), NW, and SOD) and associated sleep habits in infants aged 1 year old from the French nationwide birth cohort ELFE. This study included 11,571 infants with information on both sleep characteristics and sleep habits (parental presence when falling asleep, eating to fall asleep, sucking pacifier or finger to sleep and the location where the infant falls asleep and ends his/her sleep). Associations were studied using multinomial logistic regressions adjusted for familial and infant characteristics. Mean TST was 13hrs36 including 2hrs54 of naps, 20% of the infants had TST ≤12hrs/24h. About 46% did not present SOD or NW, while 16% had frequent SOD and 22% had NW > 1 night over 2. Parental presence, feeding to fall asleep and infants sleep location were more frequent in infants having short sleep duration (≤12h/24h), NW and SOD. Non-nutritive sucking was associated with NW, SOD and TST>14h/24h. This work provides new information regarding infant sleep location and non-nutritive sucking that should be accounted for when considering sleep behaviors. In addition, most of identified sleep habits associated with poor sleep characteristics are accessible to prevention. Key messages French infants present better sleep characteristics than their counterparts. Most sleep habits associated with poor sleep are accessible to prevention.

Objective Infant sleep plays a critical role in normal development. Sleep problems, including sleep onset difficulties (SODs) and night waking (NW), range from 20% to 30% in infants and young children and can be persistent over time up to adulthood. Young French children seem to have longer sleep durations and less sleep troubles than their counterparts worldwide. Here, we aimed at describing infant sleep characteristics (total sleep time (TST)/24 h, NW, and SODs) and associated sleep habits in infants at age one year from the French nationwide birth cohort Etude Longitudinale Francaise depuis l’Enfance (ELFE). Methods This study included 11,783 infants with information on both sleep characteristics and sleep habits (parental presence when falling asleep, eating to fall asleep, sucking a pacifier or finger to sleep and sleep arrangement and location). Associations were studied by multinomial logistic regression analyses adjusted for familial and infant characteristics. Results Mean TST was 13 h36 min including 2 h54 min of naps; 20% of the infants had TST ≤12 h/24 h. About 46% did not present SOD or NW, 16% had frequent SODs and 22% had NW > 1 night in 2. Parental presence, feeding to fall asleep and infant sleep arrangements were frequent in infants with short sleep duration (≤12 h/24 h), NW and SODs. Non-nutritive sucking was associated with risk of NW, SOD and TST >14 h/24 h. Parental room sharing was associated with NW. Conclusion This work provides new information on infant sleep arrangements and non-nutritive sucking that should be accounted for when considering sleep behaviors. In addition, most identified sleep habits associated with poor sleep characteristics may be amenable to change.

OBJECTIVE: Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcoleptic patients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls. METHODS: We included 24 children with NT1 (12.3 ± 3.6 years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2 ± 4.2 years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcoleptic patients. RESULTS: Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234 pmol/L, P < 0.001), lower t-MeHA levels (879 vs 1924 pmol/L, P < 0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P < 0.001). NT1 patients had higher BMI z-scores (2.7 ± 1.6 vs 1.0 ± 2.3, P = 0.006) and were more often obese (58% vs 29%, P = 0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P = 0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels. CONCLUSIONS: Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcoleptic children and support the use of a histaminergic therapy in the treatment against narcolepsy.

Background Few studies on the relationship between sleep quantity and/or quality and cognition have been conducted among preschoolers from the healthy general population. We aimed to identify, among 3-year-old children, early polysomnography (PSG) sleep factors associated with estimated intelligence quotient (IQ) using the Weschler Preschool and Primary Scale Intelligence-III test (WPPSI-III) and its indicators: full-scale (FISQ), verbal (VIQ), and performance (PIQ) intelligence quotients. Methods We included full-term children from the French birth-cohort AuBE with PSG recording at term (M0) and/or six months (M6), and available WPPSI-III scores at three years. Sleep and arousal characteristics of these infants were evaluated during day and night sleep periods. Relationships between IQ scores and sleep parameters were estimated using models with the child as a repeated effect adjusted for time (night/day), maturation (M0/M6), tobacco exposure (yes/no), anxiety-depressive scores during pregnancy, maternal age, duration of breastfeeding and child's gender. Results A total of 118 PSG recordings were obtained, representing a total of 78 unique children (38 with one PSG and 40 with two PSG). No correlations were found between night and day sleep durations at M0 or M6. Mean VIQ, PIQ, and FSIQ scores were within normal ranges. In multivariate models, longer sleep duration and higher sleep efficiency during the day were negatively associated with all IQ scores. More frequent arousals during the night were associated with lower VIQ scores. Conclusion Early sleep characteristics such as night sleep fragmentation or longer naps could be associated with impaired cognitive function at three years of age.

International audience; Objective. Sleep duration may vary inter-individually and intra-individually over time. We aimed at both identifying night-sleep duration (NSD) trajectories among preschoolers and studying associated factors. Methods. NSD were collected within the French birth-cohort study EDEN at ages 2, 3 and 5-6 years through parental questionnaires, and were used to model NSD trajectories among 1205 children. Familial socioeconomic factors, maternal sociodemographic, health and lifestyle characteristics as well as child health, lifestyle, and sleep characteristics at birth and/or at age 2 years were investigated in association with NSD using multinomial logistic regressions. Results. Five distinct NSD trajectories were identified: short (SS

International audience; Sleep problems affect 20% to 30% of toddlers and preschoolers. Few longitudinal studies focused on the impact of infant feeding practices on sleep. We aimed to study the associations between feeding practices up to 8 months and trajectories of sleep quantity or quality from 2 to 5-6 years. Analyses included 1028 children from the EDEN mother-child cohort. Data were collected by self-administered questionnaires. Associations between feeding practices (breastfeeding, complementary feeding, use of thickened infant formula, night feeding) and sleep trajectories (sleep onset difficulties, night waking, nighttime in bed) were analyzed by multiple logistic regressions. Predominant breastfeeding for more than 4 months was associated with lower risk for belonging to the persistent sleep onset difficulties trajectory. Night feeding at 4 months or at 2 years of age was associated with higher risk for belonging to the persistent sleep onset difficulties trajectory and night feeding at 8 months was associated with higher risk for night waking and with higher risk for short nighttime in bed. Early introduction (

Introduction Refractive errors are very common, in particular in children and adolescents, leading to global health issues, academic implications and economic costs. The process of emmetropization in child development is a multifactorial and active mechanism, and is yet to be fully understood. Light exposure and endogenous circadian rhythmicity are thought to have an important role in this process. They are also known to be both cause and consequence of various sleep habits. The study aims at investigating the role of sleep duration and timing in refractive error development of preschoolers. Methods Sleep duration and timing were assessed at age 2 and 5 years, and vision problems at age 5 through parental auto-questionnaires in 1,130 children from the EDEN birth-cohort. We performed both cross-sectional and longitudinal analyses using logistic regression models, before and after adjusting for age, sex, socio-economic status, nap duration, time spent outdoors and daily screen-time. We conducted multiple imputations to deal with missing data on covariates. The shape of the association was considered by splitting sleep duration into tertiles. Results At age 5 years, 20.4% of the children were prescribed glasses (2% for myopia, 11.9% for hyperopia and 6.8% for unknow reason). Children slept on average (SD) 11h05 (30 min) per night at age 2 and 10h49 (48 min) at age 5. Average bedtime and midsleep were 8.36 pm (30 min), 2.06 am (36 min), and 8.54 pm (30 min), 2.06 am (24 min) at age 2 and 5, respectively. In the raw longitudinal analysis, a U-shaped association was observed between nocturnal sleep duration at age 2 and eyeglass prescription at age 5: 2-years-old children sleeping 11h30 had a higher risk to have an eyeglass prescription by the age of 5. Later midsleep and bedtime at age 2 were associated with an increased risk of eyeglass prescription at age 5. All associations, except the one concerning bedtime, were barely changed after adjustment while becoming borderline significant. Conclusion Duration and timing of sleep at age 2 were associated with subsequent onset of refractive errors in preschoolers from a general population. Sleep and light hygiene might be targets for prevention. Support (if any)

Objective This preliminary study investigated electrophysiological and microstructural features of sleep in children and adolescents 4–18 years of age who were born to depressed mothers. Methods A total of 31 healthy subjects (15 male and 16 female) participated in the study. In this sample, 20 children born to mothers diagnosed with Major Depressive Disorder (MDD) were designated as “high-risk”; 11 children born to mothers without a personal history of depression were designated as “low-risk.” Polysomnography including three-channel electroencephalography (EEG) was recorded for one night at the Pediatric Sleep Unit of the University Hospital of Lyon, France. Clinical and demographic data were collected. Sleep architectural parameters were analyzed. Sleep microstructure was assessed with the scoring of cyclic alternating pattern (CAP) and CAP measures were calculated. Spectral analysis was performed, and mean EEG band power was computed for each sleep stage. Sleep electrophysiological features (slow waves and sleep spindles) were detected, and related parameters were analyzed. Data were compared between high- and low-risk groups using Student t tests. Results A reduction in low-frequency spindle activity and slow spindles spatio-temporal characteristics over frontal and central derivations, and an altered distribution of CAP phase A subtypes (reduction of A1 over A2–3 ratio) were observed in the high-risk group relative to the low-risk group. Conclusion Limited spindles generation and increased non-rapid eye movement sleep instability, observed in children born to depressed mothers, might reflect functional anomalies in cortical plasticity that could represent a pathogenic factor or an epiphenomenon for MDD.

Objective The aim was to study, with a developmental approach, the longitudinal association between night-waking from age 2 to 5–6 years and behavior at age 5–6 years. Methods Within the French birth cohort study Etude sur les Determinants pre et post natals du developpement et de la sante de l'ENfant (EDEN), repeated measures of children's night-waking were collected at age 2, 3 and 5–6 through parental questionnaires and were used to model night-waking trajectories. Behavior was assessed with the “Strengths and Difficulties Questionnaire,” which provides five subscales measuring a child's conduct problems, emotional symptoms, peer relation problems, antisocial behavior, and hyperactivity/attention problems. The behavioral subscales were dichotomized at the tenth percentile. Multivariable logistic regressions, adjusted for parents' socio-economic factors, parental characteristics, and children's characteristics and sleep habits allowed us to study, in 1143 children, the association between night-waking trajectories from 2 to 5–6 years and behavior at age 5–6 years. Results The “2 to 5–6 rare night-waking” trajectory represented 78% of the included population (n = 896), and the “2 to 5–6 common night-waking” 22% (n = 247%). Children belonging to the “2 to 5–6 common night-waking trajectory” had, at age 5–6, increased risk of presenting emotional symptoms (odds ratio [OR] = 2.17, 95% CI = 1.27–3.70, p = 0.004), conduct problems (OR = 1.63, 95% CI = 1.00–2.65, p = 0.050), and hyperactivity/attention problems (OR = 1.61, 95% CI = 1.00–2.57, p = 0.049). After adjusting for baseline behavior at age two years, only the association with emotional symptoms remained significant (OR = 2.02, 95% CI = 1.15–3.55, p = 0.015). Results did not differ according to sex. Conclusion Results suggest that the persistence of night-waking difficulties in early years is positively associated with emotional symptoms, hyperactivity/inattention, and conduct problems.

Objective This study investigated sleep architecture in newborn and six-month-old infants who were born to depressed mothers. Method Sixty-four healthy full-term infants (32 males and 32 females) participated in the study. Of these, 32 were high-risk infants who were born to mothers diagnosed with depression, and 32 were low-risk infants born to mothers without a personal history of depression. 24-hour polysomnography was recorded at zero and six months of age (M0 and M6). Sleep macro-structural parameters (total sleep time, TST; awake time; non-rapid eye movement, NREM sleep (%); rapid eye movement, REM sleep %; arousal index; and sleep efficiency) were analysed at M0 and M6. Micro-architectural sleep features (slow-wave activity, SWA; delta sleep ratio, DSR; spindle density; and rapid eye movement density) were calculated at M6. The data between high-risk and low-risk groups were compared using Student's t -tests. Results At M0 and M6, the high-risk infants showed more awake time and fewer arousals than the low-risk infants. However, the high-risk group had less NREM% at M0 and a shorter TST as well as less REM% at M6 than the low-risk group. At M6, the high-risk group showed higher SWA, higher DSR and lower spindle density in comparison with the low-risk group. Conclusions Altered sleep structure was observed during their first months of life in infants born from depressed mothers, thereby suggesting that the prenatal environment could enhance the depression vulnerability of the child and potentially decrease their neuroplasticity.

International audience; Objectives Sleep problems and deprivation are common during pregnancy, particularly in the third trimester. Previous studies are mostly descriptive or focused on specific clinical groups and late pregnancy. We aimed to identify sleep duration trajectories during the pregnancy period, their associated factors, and impact on pregnancy and birth outcomes.Methods We studied 200 women from a mother–child cohort recruited in 2009–2011 from the French general population. We used semi-parametric models to analyze data collected through questionnaires.Results: We detected three sleep duration trajectories during pregnancy: short-decreasing (8h/night, 31.6%) trajectories. Factors associated with the short-decreasing trajectory relative to the medium-decreasing trajectory were older age (odds-ratio/year = 1.13 [95%Confidence-Interval 1.00-1.29]) and working > 28 weeks of gestational age (odds-ratio = 0.30 [0.10–0.90]). Sleep duration during pregnancy in this trajectory group was modified by insomniac symptoms (regression coefficient/trimester = −0.74 [Standard-Error 0.12]) and naps (regression coefficient/trimester = 0.58 [0.25]). Restless legs syndrome was the only factor associated with the long-increasing trajectory and decreased sleep duration (regression coefficient/trimester = −0.88 [0.25]). Assisted delivery (i.e. cesarean section and/or instrumental delivery) and post-partum depression were more frequent among women with the short-decreasing and long-increasing trajectories whereas cesarean section alone was more prevalent among those with the short-decreasing trajectory. Proportion of premature births was higher in the short-decreasing trajectory group. Birth-weight-z-score was lower in the long-increasing trajectory group.Conclusion: We identified sleep trajectories among pregnant women with specific risk factors that could affect both pregnancy and birth outcomes. Taking these into consideration could improve both maternal and child health.

International audience; Night waking in preschoolers has been associated with adverse health outcomes in cross-sectional studies, but has rarely been analyzed in a longitudinal setting. Therefore, little is known about the evolution of night waking in early childhood. The objectives of the present study were: to identify night-waking trajectories in preschoolers, and to examine the risk factors associated with those trajectories. Analyses were based on the French birth-cohort study EDEN, which recruited 2002 pregnant women between 2003 and 2006. Data on a child's night waking at the ages of two, three, and five, six years, and potential confounders, were collected through parental self-reported questionnaires. Night-waking trajectories were computerized using group-based trajectory modeling on 1346 children. Two distinct developmental patterns were identified: the "2-5 rare night-waking" (77% of the children) and the "2-5 common night-waking" pattern. Logistic regressions were performed to identify the factors associated with the trajectories. Risk factors for belonging to the "2-5 common night-waking" trajectory were: exposure to passive smoking at home, daycare in a collective setting, watching television for extended periods, bottle feeding at night, high emotionality, and low shyness. This approach allowed identification of risk factors associated with night waking during a critical age window, and laid the groundwork for identifying children at higher risk of deleterious sleep patterns. Those risk factors were mainly living habits, which indicated that prevention and intervention programs could be highly beneficial in this population.

In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE) 1–3 .W e tested the hypothesis that the pathogenesis of HSE involves nonhaematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-b (IFN-b) and/or IFN-l1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-b and IFN-l1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-a or IFN-b ( IFN-a/b) but not IFN-l1. Thus, impaired TLR3- and UNC-93B-dependent IFN-a/b intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies. Childhood HSE is a rare, life-threatening, central nervous system (CNS)-restricted complication of primary infection with HSV-1, an almost ubiquitous virus that is typically innocuous 4 . Children with HSE are not unusually susceptible to other infectious agents, including viruses, or even to HSV-1-related diseases affecting sites other than the CNS 4,5 . HSV-1 reaches the CNS from the oral and nasal epithelium, via the cranial nerves 4 . We identified autosomal recessive UNC-93B deficiency as the first genetic aetiology of childhood HSE 1 . UNC-93B is required for TLR3, TLR7, TLR8 and TLR9 responses 1,6 . We then identified autosomal-recessive or autosomal-dominant deficiencies of TLR3 (refs 2 and 3), TRAF3 (ref. 7), TRIF 8 and TBK1 (ref. 9), revealing

Background Only a minority of patients with chronic hepatitis C virus (HCV) infection develops severe liver fibrosis, a process that may be controlled by human genetic factors. Objective To investigate the role of 384 single nucleotide polymorphisms (SNPs) located in 36 candidate genes related to the fibrogenesis/fibrolysis process. Methods Patients with chronic HCV infection were gathered from two French cohorts (prospectively and retrospectively). The overall sample consisted of 393 HCV-infected subjects without known risk factors for fibrosis progression, including 134 patients with severe liver fibrosis and 259 without severe fibrosis. Results Only two SNPs in strong linkage disequilibrium (LD) in the interferon γ receptor 2 gene ( IFNGR2 ) were significantly associated with liver fibrosis in both the prospective and the retrospective samples. The strongest association (p=8×10 −5 ) was observed with the G/A SNP rs9976971 with an OR of severe fibrosis for AA versus AG or GG subjects at 2.95 (95% CI 1.70 to 5.11). This effect was higher (p=9×10 −7 ) when taking into account the time of follow-up, and the hazard ratio of progression towards severe fibrosis for AA patients was 2.62 (1.76 to 3.91). Refined sequencing and analysis of the IFNGR2 region identified two additional variants in strong LD with rs9976971. No haplotypes derived from this cluster of four variants provided stronger evidence for association than rs9976971 alone. Conclusions This identification of a cluster of four IFNGR2 variants strongly associated with fibrosis progression in chronic HCV infection underlines the role of IFNγ in the development of liver fibrosis that may pave the way for new treatments.

International audience; Infection by human herpesvirus 8 (HHV-8) in childhood is common in the Mediterranean basin; however, classic Kaposi sarcoma (KS) is exceedingly rare in children not infected with HIV and not receiving immunosuppression, with only 30 cases having been reported since 1960. We recently reported 2 children with autosomal and X-linked recessive primary immunodeficiencies underlying KS in a context of multiple clinical manifestations. These reports suggested that classic KS in otherwise healthy children might also result from inborn errors of immunity more specific to HHV-8. In this article, we describe 3 unrelated Turkish children with classic KS born to first-cousin parents. The first patient, a girl, developed KS at 2 years of age with disseminated cutaneous and mucosal lesions. The clinical course progressed rapidly, and the patient died within 3 months despite treatment with vincristine. The other 2 children developed a milder form of KS at the age of 9 years, with multiple cutaneous lesions. A boy treated with interferon alpha therapy for 12 months is now in full remission at the age of 14, 2 years after treatment. The second girl is currently stabilized with etoposide, which was begun 4 months ago. None of the 3 children had any relevant familial history or other clinical features. The occurrence of classic KS in 3 unrelated Turkish children, each born to consanguineous parents, strongly suggests that autosomal recessive predisposition may drive the rare occurrence of HHV-8-associated classic KS in children.

Whole-exome sequencing reveals a homozygous splice-site mutation in the gene encoding STIM1 in a child with classic Kaposi sarcoma., Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca2+ entry. STIM1 mRNA splicing, protein production, and Ca2+ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.

Hepatitis C virus (HCV), infecting 170 million people worldwide, is a major public health problem. In developing countries, unsafe injections and blood transfusions are thought to be the major routes of transmission. However, our previous work in a population from Egypt, endemic for HCV, revealed highly significant familial correlations, strongly suggesting the existence of both familial transmission of the virus and genetic predisposition to HCV infection. We investigated the hypothesis of genetic predisposition by carrying out a segregation analysis of HCV infection in the same population. We used a logistic regression model simultaneously taking into account a major gene effect, familial correlations and relevant risk factors. We analyzed 312 pedigrees (3,703 subjects). Overall HCV seroprevalence was 11.8% and increased with age. The main associated risk factors were previous parenteral treatment for schistosomiasis and blood transfusions. We found strong evidence for a dominant major gene conferring a predisposition to HCV infection. The frequency of the predisposing allele was 0.013, reflecting a strong predisposition to HCV infection in 2.6% of the subjects, particularly those under the age of 20. This study provides evidence for the involvement of host genetic factors in susceptibility/resistance to HCV infection in endemic conditions.

Total sleep duration has been decreasing among children in the last decades. Short sleep duration (SSD) has been associated with deleterious health consequences, such as excess weight/obesity. Risk factors for SSD have already been studied among school-aged children and adolescents, but inconsistent results have been reported regarding possible gender differences. Studies reporting such relationships are scarce in preschoolers, despite the importance of this period for adopting healthy behaviour. We aimed to investigate factors associated with SSD in 3-year-old boys (n = 546) and girls (n = 482) in a French Mother-Child Cohort (EDEN Study). Children were born between 2003 and 2006 in two French university hospitals. Clinical examinations and parent self-reported questionnaires allowed us to collect sociodemographic (e.g. income, education, family situation, child-minding system), maternal [e.g. body mass index (BMI), parity, depression, breastfeeding duration] and child's characteristics (e.g. gender, birth weight, term, physical activity and TV viewing duration, food consumption, usual sleep time). Sleep duration/24-h period was calculated and SSD was defined as

International audience; AbstractBackgroundThe association between socioeconomic position and diet in early childhood has mainly been addressed based on maternal education and household income. We aimed to assess the influence of a variety of social factors from different socio-ecological levels (parents, household and child-care) on multi-time point dietary patterns identified from 2 to 5 y.MethodThis study included 974 children from the French EDEN mother-child cohort. Two multi-time point dietary patterns were derived in a previous study: they correspond to consistent exposures to either core- or non-core foods across 2, 3 and 5 y and were labelled “Guidelines” and “Processed, fast-foods”. The associations of various social factors collected during pregnancy (age, education level) or at 2-y follow-up (mother’s single status, occupation, work commitments, household financial disadvantage, presence of older siblings and child-care arrangements) with each of the two dietary patterns, were assessed by multivariable linear regression analysis.ResultsThe adherence to a diet close to “Guidelines” was positively and independently associated with both maternal and paternal education levels. The adherence to a diet consistently composed of processed and fast-foods was essentially linked with maternal variables (younger age and lower education level), household financial disadvantage, the presence of older sibling (s) and being cared for at home by someone other than the mother.ConclusionsMultiple social factors operating at different levels (parents, household, and child-care) were found to be associated with the diet of young children. Different independent predictors were found for each of the two longitudinal dietary patterns, suggesting distinct pathways of influence. Our findings further suggest that interventions promoting healthier dietary choices for young children should involve both parents and take into account not only household financial disadvantage but also maternal age, family size and options for child-care.

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1–infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-α/β and -λ antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.

International audience; Childhood multicentric Castleman disease (MCD) is a rare and unexplained lymphoproliferative disorder. We report a human herpesvirus-8 (HHV-8)-infected child, born to consanguineous Comorian parents, who displayed isolated MCD in the absence of any known immunodeficiency. We also systematically review the clinical features of the 32 children previously reported with isolated and unexplained MCD. The characteristics of this patient and the geographic areas of origin of most previous cases suggest that pediatric MCD is associated with HHV-8 infection. Moreover, as previously suggested for Kaposi sarcoma, MCD in childhood may result from inborn errors of immunity to HHV-8 infection.

Infection by human herpesvirus 8 (HHV-8), as measured by the presence of specific antibodies, was shown in countries in which HHV-8 infection is endemic to exhibit familial aggregation and a peculiar variation with age (rapid increase until puberty followed by a plateau in young adults). To investigate whether host genetic factors could explain these findings, a segregation analysis was performed of 81 families of African origin (1623 subjects; HHV-8 seroprevalence, 11.9%) living in a village in French Guiana in which HHV-8 infection is endemic. Results provide evidence for a recessive gene controlling susceptibility or resistance to HHV-8 infection. This gene is predicted to have a major effect during childhood, with almost all homozygous predisposed subjects ( approximately 6% of the population) being infected by age 15. For nonpredisposed subjects, HHV-8 infection in childhood strongly depends on virus exposure (through an HHV-8-infected mother), whereas the risk of infection appears to be low in young adults, with no evidence for heterosexual transmission.

Human herpesvirus 8 (HHV-8), also called Kaposi's sarcoma-associated herpesvirus (KSHV), is not a ubiquitous virus. In countries with a low viral seroprevalence (< 5% in adult general population) as the USA, Northern Europe and Asia, the infection concerns essentially homosexual men. In this latter population, the viral transmission seems to occur during sex. In endemic countries (HHV-8 seroprevalence between 10-70% in the adult general population) as in the Mediterranean basin (Italy, Greece), and Africa (East and Central Africa), men, women and children are infected. In these countries, HHV-8 seroprevalence increases with age and often reaches adult rates before the end of puberty. Viral transmission, in general endemic populations, seems to occur from mother to child and between sibs whereas heterosexual transmission appears to concern essentially groups at risk for sexual transmitted diseases. Saliva is a major reservoir of HHV-8.

Night shift work has been associated with an increased risk of breast cancer pointing to a role of circadian disruption. We investigated the role of circadian clock gene polymorphisms and their interaction with nightwork in breast cancer risk in a population-based case–control study in France including 1126 breast cancer cases and 1174 controls. We estimated breast cancer risk associated with each of the 577 single nucleotide polymorphisms (SNPs) in 23 circadian clock genes. We also used a gene- and pathway-based approach to investigate the overall effect on breast cancer of circadian clock gene variants that might not be detected in analyses based on individual SNPs. Interactions with nightwork were tested at the SNP, gene, and pathway levels. We found that two SNPs inRORA(rs1482057 and rs12914272) were associated with breast cancer in the whole sample and among postmenopausal women. In this subpopulation, we also reported an association with rs11932595 inCLOCK, and withCLOCK,RORA, andNPAS2in the analyses at the gene level. Breast cancer risk in postmenopausal women was also associated with overall genetic variation in the circadian gene pathway (P=0.04), but this association was not detected in premenopausal women. There was some evidence of an interaction betweenPER1and nightwork in breast cancer in the whole sample (P=0.024), although the effect was not statistically significant after correcting for multiple testing (P=0.452). Our results support the hypothesis that circadian clock gene variants modulate breast cancer risk.

Objective: Several studies, mainly in animals, but also in humans, have shown that diet in infancy is associated with differences in blood cholesterol concentrations later in life. The objective was to examine this relationship in children aged 5–11 y after taking into account their current diet and parental hypercholesterolemia. Setting and subjects: 251 prepubertal boys and 223 prepubertal girls enrolled in the schools in two little towns in northern France. Design and methods: Cross-sectional evaluation including measurements of cholesterol concentrations on capillary blood and a single weekday food intake record. Infant feeding patterns were obtained by questionnaire given to the mothers Results: 50% of the children had been breast-fed for a median duration of less than 2 months. Cow’s milk was introduced in the diet as whole milk for 33% of the children. After adjustment for age, height, and sibship, capillary cholesterol concentration was lower in boys who had been breast fed (geometric mean: 4.4, 95% confidence interval of the mean: 4.2–4.6 mmol/L) than in those fed with formula (4.7, 4.5–4.8 mmol/L, P

To determine the epidemiological characteristics of human T cell leukemia/lymphoma virus type I (HTLV-I) infection in the endemic village of Maripasoula, French Guiana, 1,614 persons (83.2% of the population) aged 2 to 91 years (mean age 21) were studied from November 1994 through April 1995. Plasma samples were screened by an HTLV-I ELISA and an IFA test (on MT2 cells), and positive samples were tested by an HTLV-I and -II type-specific Western blot. Overall seropositivity in the village was 6.7%, but HTLV-I infection was restricted to 3 of 6 ethnic groups, including the Noir-Marron (descendants of escaped African slaves, 8%), the Creoles (4.1%) and those of mixed Noir Marron/other ethnicity (3.6%). In the Noir-Marron population of 1,222 persons, including 606 men and 616 women and representing 76% of those tested, HTLV-I seroprevalence increased significantly with age in both sexes, reaching 40% in women older than 50 years. Univariate risk factors for HTLV-I seropositivity in women included older age, more pregnancies, more live births and a history of hospitalization. A cross-sectional analysis of sexual partners demonstrated an excess of discordant female HTLV-I+/male HTLV-I- couples, indicating preferential male-to-female sexual transmission. The demonstration of II HTLV-I-seropositive children aged less than 15 years, of whom 9 had a seropositive mother, suggested maternal-child HTLV-I transmission. Our results demonstrate a very high seroprevalence of HTLV-I in this South American population descended from African slaves, probably due to high rates of mother-to-child and sexual transmission within this rather isolated group.

Background KSHV/HHV-8 is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma and most multicentric Castleman's disease cases. KSHV exhibits a high genetic variability comprising five genotypes (A–E). Few data are yet available concerning the situation of KSHV, its genetic variability and the associated diseases in Melanesia. Objectives We performed a study on 626 natives Melanesians from New Caledonia and Vanikoro Island to evaluate KSHV seroprevalence and characterize molecularly the viral strains. Study design Plasma from 343 males and 283 females (age range: 15–86 years, mean age: 60) were tested for KSHV latent antibodies by an immunofluorescence assay (IFA) using BC-3 cells. DNAs extracted from peripheral blood buffy-coat of KSHV seropositive individuals were amplified to obtain a 737-bp fragment of the ORF-K1 gene. Phylogenetic analyses were then performed. Results Among 626 samples, 148 were IFA positive (dilution ≥ 1:80). The overall seroprevalence was 23.6% (25.2% in New Caledonia, 17.5% in Vanikoro). Fifteen (8 men and 7 women, mean age 69 years) out of 148 DNA samples were found PCR positive. All ORF-K1 sequences belonged to KSHV genotype D. A geographic clustering according to the island of origin of KSHV infected persons was clearly observed with sequences from New Caledonia clustering with most Vanuatu strains. Conclusions New Caledonia and Vanikoro are endemic for KSHV with a high diversity of genotype D variants. These strains were probably introduced into New Caledonia during multiple waves of migrations of Melanesian and Polynesian individuals that have colonized this archipelago.

Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1–infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood.

A new autosomal recessive form of complete TLR3 deficiency reveals that human TLR3 is nonredundant in immunity against herpes simplex virus 1 in the central nervous system (CNS) but redundant in host defense against viruses outside the CNS., Autosomal dominant TLR3 deficiency has been identified as a genetic etiology of childhood herpes simplex virus 1 (HSV-1) encephalitis (HSE). This defect is partial, as it results in impaired, but not abolished induction of IFN-β and -λ in fibroblasts in response to TLR3 stimulation. The apparently normal resistance of these patients to other infections, viral illnesses in particular, may thus result from residual TLR3 responses. We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient’s fibroblasts with HSV-1, the impairment of IFN-β and -λ production resulted in high levels of viral replication and cell death. In contrast, the patient’s peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14+ and/or CD16+ monocytes, plasmacytoid dendritic cells, and in vitro derived monocyte-derived macrophages, responded normally to both poly(I:C) and HSV-1, with the induction of antiviral IFN production. These findings identify a new genetic etiology for childhood HSE, indicating that TLR3-mediated immunity is essential for protective immunity to HSV-1 in the central nervous system (CNS) during primary infection in childhood, in at least some patients. They also indicate that human TLR3 is largely redundant for responses to double-stranded RNA and HSV-1 in various leukocytes, probably accounting for the redundancy of TLR3 for host defense against viruses, including HSV-1, outside the CNS.

Material and methods In the framework of ongoing projets on HTLV-1/2 and related viruses in central Africa, we systematically analysed by WB, plasma from villagers living in south Cameroun. The studied group included 2155 individuals (mean age 44, range 2-90, 982 women/1173 men), either Bantous (1258) or Pygmies (897). All plasma samples were tested by WB (HTLV 2-4 MPD) with interpretation done according to manufacturer instructions. Only clear bands were considered as positive/informative. DNA extracted from buffy-coat were subjected to PCR using several primer pairs known to detect HTLV-1/2/ 3/4. Positive PCR bands were sequenced.