Matched Control Children Research Articles

Childhood Maltreatment and Biological Aging in Middle Adulthood: The Role of Psychiatric Symptoms

BackgroundChildhood maltreatment and psychiatric morbidity have each been associated with accelerated biological aging primarily through cross-sectional studies. Using data from a prospective longitudinal study of individuals with histories of childhood maltreatment and control participants followed into midlife, we tested 2 hypotheses examining whether 1) psychiatric symptoms mediate the relationship between childhood maltreatment and biological aging and 2) psychiatric symptoms of anxiety, depression, or posttraumatic stress disorder (PTSD) act in conjunction with childhood maltreatment to exacerbate the association of child maltreatment to aging. MethodsChildren (ages 0–11 years) with documented histories of maltreatment and demographically matched control children were followed into adulthood (N = 607) and interviewed over several waves of the study. Depression, anxiety, and PTSD symptoms were assessed at mean ages of 29 (interview 1) and 40 (interview 2) years. Biological age was measured from blood chemistries collected later (mean age = 41 years) using the Klemera-Doubal method. Hypotheses were tested using linear regressions and path analyses. ResultsAdults with documented histories of childhood maltreatment showed more symptoms of depression, PTSD, and anxiety at both interviews and more advanced biological aging, compared with control participants. PTSD symptoms at both interviews and depression and anxiety symptoms only at interview 2 predicted accelerated biological aging. There was no evidence of mediation; however, anxiety and depression moderated the relationship between childhood maltreatment and biological aging. ConclusionsThese new findings reveal the shorter- and longer-term longitudinal impact of PTSD on biological aging and the amplifying effect of anxiety and depression on the relationship between child maltreatment and biological aging.

Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection

Although the genetic basis and pathogenesis of type 1 diabetes have been studied extensively, how host responses to environmental factors might contribute to autoantibody development remains largely unknown. Here, we use longitudinal blood transcriptome sequencing data to characterize host responses in children within 12 months prior to the appearance of type 1 diabetes-linked islet autoantibodies, as well as matched control children. We report that children who present with insulin-specific autoantibodies first have distinct transcriptional profiles from those who develop GADA autoantibodies first. In particular, gene dosage-driven expression of GSTM1 is associated with GADA autoantibody positivity. Moreover, compared with controls, we observe increased monocyte and decreased B cell proportions 9-12 months prior to autoantibody positivity, especially in children who developed antibodies against insulin first. Lastly, we show that control children present transcriptional signatures consistent with robust immune responses to enterovirus infection, whereas children who later developed islet autoimmunity do not. These findings highlight distinct immune-related transcriptomic differences between case and control children prior to case progression to islet autoimmunity and uncover deficient antiviral response in children who later develop islet autoimmunity.

Failure to thrive in toddlers with lack of interest in eating and food and their cognitive development during later childhood.

Experiencing Failure to Thrive or malnutrition in early years has been associated with children later displaying low Intelligence Quotient (IQ). The current study's aim was to examine whether Failure to Thrive in Toddlers with Lack of Interest in Eating and Food, a subtype of Avoidant/Restrictive Food Intake Disorder as defined by DSM-5, which has also previously been identified as Infantile Anorexia (IA), was associated with poor cognitive development outcomes during later childhood. The IQs and growth parameter of 30 children (53% female) previously diagnosed and treated for IA at 12 to 42 months of age, were reevaluated at a mean age of 10.0 years (SD = 2.1 years) and compared to 30 matched control children. Children's growth was assessed using Z-scores and their cognitive development was measured using the Wechsler Intelligence Scale for Children-4th Edition. None of the growth parameters were significantly related to IQ. Further, IQ scores of children previously diagnosed with IA and control children were not significantly different. However, the education level of children's fathers had a significantly positive effect on IQ. Our study highlights the disjunction between growth parameters and IQ within our sample. Overall, our findings suggest that the primary target of intervention for these children should be the parent-child conflict around the feeding relationship, rather than a focus on the child's weight itself. Finally, our results confirm the relevance to include fathers in the intervention of these children.

Protocol for a nested case-control study design for omics investigations in the Environmental Determinants of Islet Autoimmunity cohort

Background: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D. Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case’s onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood. Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation. KEY MESSAGES The ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

The effects of sleep disordered breathing on sleep spindle activity in children and the relationship with sleep, behavior and neurocognition

Study objectivesObstructive sleep disordered breathing (SDB), has adverse neurocognitive and behavioral sequelae in children, despite conventional measures of sleep disruption being unaffected. There is growing evidence that sleep spindles may serve as a more sensitive marker of sleep quality. We investigated the relationship between sleep spindles and sleep fragmentation and neurocognition across the spectrum of SDB severity in children. MethodsChildren 3–12 years old referred for clinical assessment of SDB and age matched control children from the community were recruited and underwent polysomnography. Sleep spindles were identified manually during N2 and N3 sleep. Spindle activity was characterised as spindle number, density (number of spindles/h) and intensity (spindle density x average spindle duration). Children completed a battery of tests assessing global intellectual ability, language, attention, visuospatial ability, sensorimotor skills, adaptive behaviors and skills and problem behaviors and emotional difficulties. ResultsChildren were grouped into control, Primary Snoring, Mild OSA and Moderate/severe OSA, N = 10/group. All measures of spindle activity were lower in the SDB groups compared to the Control children and this reached statistical significance for Mild OSA (p < 0.05 for all). Higher spindle indices were associated with better performance on executive function and visual ability assessments but poorer performance on auditory attention and communication skills. Higher spindle indices were associated with better behavior. ConclusionThe reduced spindle activity observed in the children with SDB, particularly Mild OSA, indicates that sleep micro-architecture is disrupted and that this disruption may underpin the negative effects of SDB on attention, learning and memory.

O069 The effects of sleep disordered breathing on sleep spindle activity in children and the relationship with neurocognition

Abstract Introduction Conventional sleep macro-architecture measures of sleep disruption have not been associated with the adverse neurocognitive sequelae of sleep disordered breathing (SDB). Sleep spindles protecting the sleeping brain from external sensory stimuli and can serve as markers of sleep integrity. We investigated the relationship between sleep spindles and sleep fragmentation and neurocognition across the spectrum of SDB in children. Methods Children 3-12y referred for clinical assessment of SDB and age matched control children from the community were recruited. Sleep spindles were identified manually during N2 and N3 sleep. Spindle activity was characterised as spindle number, spindle density (number of spindles/ h) and spindle intensity (spindle density x average spindle duration). The Stanford-Binet Intelligence Scales measured global intellectual ability and the NeuroPSYchological assessment (NEPSY-II) measured language, attention, visuospatial ability and sensorimotor skills. Results Children were grouped into control, Primary Snoring, Mild OSA and Moderate/severe OSA, N=10/ group. All measures of spindle activity were lower in the SDB groups compared to the Control children and this reached statistical significance for Mild OSA (p&amp;lt;0.05 for all). Spindle activity was not correlated with any measure of the Stanford-Binet. Overall, all measures of spindle activity were positively correlated with the Design Copy and the Inhibition Naming combined scale score and negatively correlated with Auditory Attention subscales of the NEPSY-II. Conclusion The reduced spindle activity observed in the children with SDB, particularly Mild OSA, indicates that sleep micro-architecture is disrupted and that this disruption may underpin the negative effects of SDB on attention, learning and memory.

Sex differences in regional gray matter density in pre-adolescent binge eating disorder: a voxel-based morphometry study.

Binge eating disorder (BED) is a pernicious psychiatric disorder which is linked with broad medical and psychiatric morbidity, and obesity. While BED may be characterized by altered cortical morphometry, no evidence to date examined possible sex-differences in regional gray matter characteristics among those with BED. This is especially important to consider in children, where BED symptoms often emerge coincident with rapid gray matter maturation. Pre-adolescent, 9-10-year old boys (N = 38) and girls (N = 33) with BED were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development Study. We investigated sex differences in gray matter density (GMD) via voxel-based morphometry. Control sex differences were also assessed in age and body mass index and developmentally matched control children (boys N = 36; girls N = 38). Among children with BED, we additionally assessed the association between dorsolateral prefrontal (dlPFC) GMD and parent-reported behavioral approach and inhibition tendencies. Girls with BED uniquely demonstrate diffuse clusters of greater GMD (p < 0.05, Threshold Free Cluster Enhancement corrected) in the (i) left dlPFC (p = 0.003), (ii) bilateral dmPFC (p = 0.004), (iii) bilateral primary motor and somatosensory cortex (p = 0.0003) and (iv) bilateral precuneus (p = 0.007). Brain-behavioral associations suggest a unique negative correlation between GMD in the left dlPFC and behavioral approach tendencies among girls with BED. Early-onset BED may be characterized by regional sex differences in terms of its underlying gray matter morphometry.

Aberrant Emotional Prosody Circuitry Predicts Social Communication Impairments in Children With Autism

BackgroundEmotional prosody provides acoustical cues that reflect a communication partner’s emotional state and is crucial for successful social interactions. Many children with autism have deficits in recognizing emotions from voices; however, the neural basis for these impairments is unknown. We examined brain circuit features underlying emotional prosody processing deficits and their relationship to clinical symptoms of autism. MethodsWe used an event-related functional magnetic resonance imaging task to measure neural activity and connectivity during processing of sad and happy emotional prosody and neutral speech in 22 children with autism and 21 matched control children (7–12 years old). We employed functional connectivity analyses to test competing theoretical accounts that attribute emotional prosody impairments to either sensory processing deficits in auditory cortex or theory of mind deficits instantiated in the temporoparietal junction (TPJ). ResultsChildren with autism showed specific behavioral impairments for recognizing emotions from voices. They also showed aberrant functional connectivity between voice-sensitive auditory cortex and the bilateral TPJ during emotional prosody processing. Neural activity in the bilateral TPJ during processing of both sad and happy emotional prosody stimuli was associated with social communication impairments in children with autism. In contrast, activity and decoding of emotional prosody in auditory cortex was comparable between autism and control groups and did not predict social communication impairments. ConclusionsOur findings support a social-cognitive deficit model of autism by identifying a role for TPJ dysfunction during emotional prosody processing. Our study underscores the importance of tuning in to vocal-emotional cues for building social connections in children with autism.

Vitamin D deficiency and vitamin D receptor FokI polymorphism as risk factors for COVID-19

BackgroundGiven the sparse data on vitamin D status in pediatric COVID-19, we investigated whether vitamin D deficiency could be a risk factor for susceptibility to COVID-19 in Egyptian children and adolescents. We also investigated whether vitamin D receptor (VDR) FokI polymorphism could be a genetic marker for COVID-19 susceptibility.MethodsOne hundred and eighty patients diagnosed to have COVID‐19 and 200 matched control children and adolescents were recruited. Patients were laboratory confirmed as SARS-CoV-2 positive by real-time RT-PCR. All participants were genotyped for VDR Fok1 polymorphism by RT-PCR. Vitamin D status was defined as sufficient for serum 25(OH) D at least 30 ng/mL, insufficient at 21–29 ng/mL, deficient at <20 ng/mL.ResultsNinety-four patients (52%) had low vitamin D levels with 74 (41%) being deficient and 20 (11%) had vitamin D insufficiency. Vitamin D deficiency was associated with 2.6-fold increased risk for COVID-19 (OR = 2.6; [95% CI 1.96–4.9]; P = 0.002. The FokI FF genotype was significantly more represented in patients compared to control group (OR = 4.05; [95% CI: 1.95–8.55]; P < 0.001).ConclusionsVitamin D deficiency and VDR Fok I polymorphism may constitute independent risk factors for susceptibility to COVID-19 in Egyptian children and adolescents.ImpactVitamin D deficiency could be a modifiable risk factor for COVID-19 in children and adolescents because of its immune-modulatory action.To our knowledge, ours is the first such study to investigate the VDR Fok I polymorphism in Caucasian children and adolescents with COVID-19.Vitamin D deficiency and the VDR Fok I polymorphism may constitute independent risk factors for susceptibility to COVID-19 in Egyptian children and adolescents.Clinical trials should be urgently conducted to test for causality and to evaluate the efficacy of vitamin D supplementation for prophylaxis and treatment of COVID-19 taking into account the VDR polymorphisms.

Musical abilities in children with developmental cerebellar anomalies.

Developmental Cerebellar Anomalies (DCA) are rare diseases (e.g., Joubert syndrome) that affect various motor and non-motor functions during childhood. The present study examined whether music perception and production are affected in children with DCA. Sixteen children with DCA and 37 healthy matched control children were tested with the Montreal Battery for Evaluation of Musical Abilities (MBEMA) to assess musical perception. Musical production was assessed using two singing tasks: a pitch-matching task and a melodic reproduction task. Mixed model analyses showed that children with DCA were impaired on the MBEMA rhythm perception subtest, whereas there was no difference between the two groups on the melodic perception subtest. Children with DCA were also impaired in the melodic reproduction task. In both groups, singing performance was positively correlated with rhythmic and melodic perception scores, and a strong correlation was found between singing ability and oro-bucco-facial praxis in children with DCA. Overall, children with DCA showed impairments in both music perception and production, although heterogeneity in cerebellar patient's profiles was highlighted by individual analyses. These results confirm the role of the cerebellum in rhythm processing as well as in the vocal sensorimotor loop in a developmental perspective. Rhythmic deficits in cerebellar patients are discussed in light of recent work on predictive timing networks including the cerebellum. Our results open innovative remediation perspectives aiming at improving perceptual and/or production musical abilities while considering the heterogeneity of patients' clinical profiles to design music-based therapies.

Hospitalization and comorbidity in children with type 2 diabetes.

To describe hospitalization rates and reasons for hospitalization in children with type 2 diabetes (T2D) and to compare these rates to a matched cohort without diabetes and to children with type 1 diabetes (T1D). Population-based cohorts of 528 children (7-18 years of age) with prevalent T2D, 1519 matched control children without diabetes and 778 children with T1D were identified from a clinical registry and linked to health care records to assess hospitalizations and reasons for hospitalizations using ICD-9CM and ICD-10CA codes. Children with T2D are more likely than their matched controls and children with T1D to be admitted to hospital in the year prior to diagnosis {RR 2.83 (1.77, 4.53) p < 0.0001 and 8.05 (4.05, 16.00) p < 0.0001, respectively}, in the first year post diagnosis {RR 3.19 (2.08, 4.89) p < 0.0001 and 3.04 (1.86, 4.98) p < 0.0001, respectively} and in the 5 year post diagnosis period {RR 1.99 (1.56, 2.53) p < 0.0001 and 1.91 (1.48, 2.46) p < 0.0001, respectively}. Mental illness was the most common cause for hospital admission in both children with T2D and their matched controls. This differs from children with T1D where endocrine causes constitute the most common reason for hospital admission. This analysis provides novel data on hospitalization rates and diagnoses in the increasing population of children with T2D. This information is important to inform health care programming and health policy planning to best meet the needs of this population.

Childhood Maltreatment, Blood Lead Levels, and Crime and Violence: A Prospective Examination

BackgroundResearch has shown that maltreated children are at increased risk for subsequent crime and violence and are more likely to reside in neighborhoods with a high likelihood of lead exposure. Other literature has reported associations between childhood lead exposure and antisocial and criminal behavior. Little is known about the relationships among childhood maltreatment, adult lead exposure, and crime and violence. MethodsAs part of a prospective longitudinal study of the long-term consequences of childhood maltreatment, children with documented histories of abuse and neglect and demographically matched control children (ages 0–11 years) were followed into adulthood and interviewed. Participants included 556 individuals who had valid blood lead level (BLL) measures at a mean age of 41.2 years. Participants had a mean age of 50.5 (SD = 3.53) years at the time of the last criminal history check used to determine the number of arrests. ResultsChildhood maltreatment predicted a higher number of arrests for any crime and any violence after the blood was collected but not higher BLLs in adulthood. There were significant paths from adult BLLs to arrests after the blood was collected, despite controlling for age, sex, race, and IQ and the inclusion of individual- and neighborhood-level socioeconomic status, and paths from neighborhood socioeconomic status to higher BLLs in models predicting any arrest and any violent arrest after the blood was collected. ConclusionsThese findings demonstrate how environmental toxins such as lead can affect outcomes in adulthood, including crime, and provide evidence that links neighborhood disadvantage to higher BLLs in adulthood.

Aberrant functional connectivity between reward and inhibitory control networks in pre-adolescent binge eating disorder.

Behavioral features of binge eating disorder (BED) suggest abnormalities in reward and inhibitory control. Studies of adult populations suggest functional abnormalities in reward and inhibitory control networks. Despite behavioral markers often developing in children, the neurobiology of pediatric BED remains unstudied. 58 pre-adolescent children (aged 9-10-years) with BED (mBMI = 25.05; s.d. = 5.40) and 66 age, BMI and developmentally matched control children (mBMI = 25.78; s.d. = 0.33) were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development (ABCD) Study. We investigated group differences in resting-state functional MRI functional connectivity (FC) within and between reward and inhibitory control networks. A seed-based approach was employed to assess nodes in the reward [orbitofrontal cortex (OFC), nucleus accumbens, amygdala] and inhibitory control [dorsolateral prefrontal cortex, anterior cingulate cortex (ACC)] networks via hypothesis-driven seed-to-seed analyses, and secondary seed-to-voxel analyses. Findings revealed reduced FC between the dlPFC and amygdala, and between the ACC and OFC in pre-adolescent children with BED, relative to controls. These findings indicating aberrant connectivity between nodes of inhibitory control and reward networks were corroborated by the whole-brain FC analyses. Early-onset BED may be characterized by diffuse abnormalities in the functional synergy between reward and cognitive control networks, without perturbations within reward and inhibitory control networks, respectively. The decreased capacity to regulate a reward-driven pursuit of hedonic foods, which is characteristic of BED, may in part, rest on this dysconnectivity between reward and inhibitory control networks.

Regional gray matter abnormalities in pre-adolescent binge eating disorder: A voxel-based morphometry study

BackgroundBinge eating disorder (BED) is a pernicious psychiatric disorder which is linked with an array of multisystemic organ morbidity, broad psychiatric morbidity, and obesity. Despite behavioral markers often developing in early childhood, the neurobiological markers of early-onset BED remain understudied, and developmental pathophysiology remains poorly understood. Methods71 preadolescent children (aged 9–10-years) with BED and 74 age, BMI and developmentally matched control children were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development (ABCD) Study. We investigated group differences in gray matter density (GMD) via voxel-based morphometry (VBM). We additionally performed region of interest analyses, assessing the association between GMD in nodes of the reward (orbitofrontal cortex; OFC) and inhibitory control (dorsolateral prefrontal cortex; dlPFC) networks, and parent-reported behavioral inhibition and approach tendencies. ResultsDiffuse elevations in cortical GMD were noted in those with BED, which spanned prefrontal, parietal, and temporal regions. No areas of reduced GMD were noted in those with BED. No alterations in subcortical GMD were noted. Brain-behavioral associations suggest a distinct and negative relationship between GMD in the OFC and dlPFC, respectively, and self-reported markers of hedonic behavioral approach tendencies. ConclusionsEarly-onset BED may be characterized by diffuse morphological abnormalities in gray matter density, suggesting alterations in cortical architecture which may reflect decreased synaptic pruning and arborization, or decreased myelinated fibers and therefore inter-regional afferents.

Is the Motor Impairment in Attention Deficit Hyperactivity Disorder (ADHD) a Co-Occurring Deficit or a Phenotypic Characteristic?

ObjectivesMotor difficulties are often reported in individuals with attention deficit hyperactivity disorder (ADHD). The aims of this study are to detail the motor profile of children with ADHD and to determine whether the motor impairment present in a large proportion of children with ADHD represents a phenotypic characteristic of ADHD or a co-occurring deficit.MethodsParticipants with ADHD (N = 51; age 8 to 15 years) and typically developing (TD) motor matched control children (N = 75; age 4 to 11 years) completed the largest battery of assessments of motor function that have been used with this population to date, as well as a measure of inhibition as a behavioural measure of ADHD characteristics. Parents/caregivers also completed questionnaires relating to ADHD symptomology and a retrospective report of their child’s motor milestone achievement.ResultsA motor deficit was observed in 47% of our ADHD sample. Few relationships were observed between ADHD core characteristics and motor competence. Furthermore, there was an uneven profile of motor performance across different motor tasks, relative to the TD children. Interestingly, it appears that motor milestone achievement is not delayed in ADHD.ConclusionsOur findings suggest that the motor deficit observed in ADHD is not inherent to ADHD. The motor deficit observed in some children with ADHD does not represent a simple delay in development and is not observed in infancy with respect to reaching motor milestones.

Association of interleukin-17A gene polymorphisms and susceptibility to systemic lupus erythematosus in Egyptian children and adolescents: a multi-centre study.

Recently, the interleukin-17A (IL-17A) gene has emerged as a potential candidate gene for autoimmune disorders, including systemic lupus erythematosus (SLE). This study aimed to investigate whether IL-17A polymorphisms at rs2275913 G/A, rs8193036 C/T and rs3748067 C/T could be susceptibility markers for juvenile-onset SLE (JSLE) and lupus nephritis (LN) in Egyptian children and adolescents. In this multi-centre study, we genotyped 320 patients diagnosed with JSLE and 320 matched control children for three IL-17A polymorphisms at rs2275913 G/A, rs8193036 C/T and rs3748067 C/T using TaqMan probe-based real-time polymerase chain reaction. Meanwhile, IL-17A serum levels were assessed using ELISA. The IL-17 rs2275913 A/A genotype and A allele were more represented in JSLE patients compared to the control group (21% vs. 7%, odds ratio (OR) = 3.8, 95% confidence interval (CI) 1.78-5.5, p = 0.001, pBonf = 0.003 for the A/A genotype; 37% vs. 29%, OR = 1.4, 95% CI 1.11-1.8, p = 0.003, pBonf = 0.009 for the A allele. No significant difference was found for IL-17 rs8193036 and rs3748067 single nucleotide polymorphisms (SNPs) in genotype distribution or allele frequencies (p>0.05). Patients carrying the IL-17 rs2275913 A/A genotype and A allele were more likely to develop LN (OR = 5.64, 95% CI 2.39-13.77, pBonf = 0.001 for the A/A genotype; OR = 2.73, 95% CI 1.84-4.07, pBonf = 0.02 for the A allele). The IL-17 rs2275913 A allele and A/A genotype were associated with high IL-17 serum levels and may contribute to susceptibility to JSLE and the development of LN in Egyptian children and adolescents. However, no significant association was evident between the studied IL-17A SNPs and other clinical phenotypes, disease activity scores or laboratory profile of JSLE.

Diarrhoeal disease and subsequent risk of death in infants and children residing in low-income and middle-income countries: analysis of the GEMS case-control study and 12-month GEMS-1A follow-on study

SummaryBackgroundThe Global Enteric Multicenter Study (GEMS) was a 3-year case-control study that measured the burden, aetiology, and consequences of moderate-to-severe diarrhoea (MSD) in children aged 0–59 months. GEMS-1A, a 12-month follow-on study, comprised two parallel case-control studies, one assessing MSD and the other less-severe diarrhoea (LSD). In this report, we analyse the risk of death with each diarrhoea type and the specific pathogens associated with fatal outcomes.MethodsGEMS was a prospective, age-stratified, matched case-control study done at seven sites in Africa and Asia. Children aged 0–59 months with MSD seeking care at sentinel health centres were recruited along with one to three randomly selected matched community control children without diarrhoea. In the 12-month GEMS-1A follow-on study, children with LSD and matched controls, in addition to children with MSD and matched controls, were recruited at six of the seven sites; only cases of MSD and controls were enrolled at the seventh site. We compared risk of death during the period between enrolment and one follow-up household visit done about 60 days later (range 50–90 days) in children with MSD and LSD and in their respective controls. Approximately 50 pathogens were detected using, as appropriate, classic bacteriology, immunoassays, gel-based PCR and reverse transcriptase PCR, and quantitative real-time PCR (qPCR). Specimens from a subset of GEMS cases and controls were also tested by a TaqMan Array Card that compartmentalised probe-based qPCR for 32 enteropathogens.Findings223 (2·0%) of 11 108 children with MSD and 43 (0·3%) of 16 369 matched controls died between study enrolment and the follow-up visit at about 60 days (hazard ratio [HR] 8·16, 95% CI 5·69–11·68, p<0·0001). 12 (0·4%) of 2962 children with LSD and seven (0·2%) of 4074 matched controls died during the follow-up period (HR 2·78, 95% CI 0·95–8·11, p=0·061). Risk of death was lower in children with dysenteric MSD than in children with non-dysenteric MSD (HR 0·20, 95% CI 0·05–0·87, p=0·032), and lower in children with LSD than in those with non-dysenteric MSD (HR 0·29, 0·14–0·59, p=0·0006). In children younger than 24 months with MSD, infection with typical enteropathogenic Escherichia coli, enterotoxigenic E coli encoding heat-stable toxin, enteroaggregative E coli, Shigella spp (non-dysentery cases), Aeromonas spp, Cryptosporidium spp, and Entamoeba histolytica increased risk of death. Of 61 deaths in children aged 12–59 months with non-dysenteric MSD, 31 occurred among 942 children qPCR-positive for Shigella spp and 30 deaths occurred in 1384 qPCR-negative children (HR 2·2, 95% CI 1·2–3·9, p=0·0090), showing that Shigella was strongly associated with increased risk of death.InterpretationRisk of death is increased following MSD and, to a lesser extent, LSD. Considering there are approximately three times more cases of LSD than MSD in the population, more deaths are expected among children with LSD than in those with MSD. Because the major attributable LSD-associated and MSD-associated pathogens are the same, implementing vaccines and rapid diagnosis and treatment interventions against these major pathogens are rational investments.FundingBill & Melinda Gates Foundation.

Geochemical exposure of heavy metals in environmental samples from the vicinity of old gas mining area in northern part of Sindh Pakistan. Adverse impact on children

In early nineteen century, a gas field was operational in southern part of Sindh, Pakistan for power production. The plant was completely un-operational for last three decades, whereas all wastage and raw materials are still dumped there, which might be the source to contaminate the ground water. The most of the workers population still living in different villages nearby the gas field. In present study, evaluated the undesirable effects of the toxic metals (lead and cadmium) via consuming groundwater for drinking and other domestic purpose especially in children of ≤5.0 years. For comparative purpose groundwater of nonindustrial area (nonexposed) was also analysed and their impact on age matched children was carried out. Biological samples (scalp hair and blood) were collected from children of exposed and nonexposed areas. The Cd and Pb in scalp hair and blood samples were carried out by graphite furnace atomic absorption spectrometry. Whereas, Cd and Pb in groundwater obtained from both areas were determined prior to applied preconcentration method as reported in our previous works. The Cd and Pb contents in the groundwater of villages of exposed area were found in the range of 5.18–10.9 and 19.9–69.5 μg/L, respectively. Whereas, the groundwater of nonexposed area contains Cd and Pb in the range of 1.79–3.78 and 5.07–24.3 μg/L, respectively. It was observed that the concentrations of Cd and Pb in scalp hair and blood samples of children belongs to exposed area have ≥2.0 fold higher than the resulted data attained for age matched control children, indicating as the exposure biomarkers of toxic metals. The children belong to exposed area have poor health, anemic and low body mass index (<13 kg/m2). A significant positive correlations among Cd and Pb concentrations in biological samples of exposed subjects and groundwater was observed (p < 0.01).

Influence of early adversity on cortisol reactivity, SLC6A4 methylation and externalizing behavior in children of alcoholics

BackgroundChildren of parents with alcoholism face considerable stress, and often have externalizing behaviors. Early adversity is known to affect DNA methylation and the functioning of the HPA axis. We investigated the association of early adversity with cortisol reactivity, 5HTTLPR genotype, site specific DNA methylation in the SLC6A4 gene and externalizing behavior in children of alcoholics (COA), and a matched sample of control children. MethodsWe examined children of alcoholics (N = 50) and age matched control children (N = 50) for exposure to early adversity (both prenatal and postnatal), assessed their salivary cortisol reactivity and evaluated their levels of emotional and behavioral difficulty in terms of externalizing and internalizing behavior. Site-specific DNA methylation at a previously characterized SLC6A4 region was determined in salivary DNA using pyrosequencing. The 5HTTLPR region of the SLC6A4 gene was also genotyped. ResultsCOA had significantly higher experience of early adversity than control children. Cortisol reactivity was reduced in COA, and negatively correlated with early adversity. Both early adversity and cortisol reactivity correlated with externalizing behavior. SLC6A4 methylation was higher in COA, and correlated with early adversity. SLC6A4 genotype did not show association with any of the variables. ConclusionOur study provides further evidence that early adversity is associated with blunted cortisol reactivity, increased site-specific CpG DNA methylation at the SLC6A4 gene, and high externalizing behavior.

Survival analysis of adult and children intermittent exotropia using a matched case-control design

To compare the surgical outcomes of adult intermittent exotropia (X(T)) patients and matched control children X(T) patients including survival analysis. Fifty-two adult X(T) patients and 129 matched control children X(T) patients were included. Clinical characteristics, survival analysis, and surgical dose-response curves were evaluated and compared between the two groups. The weighted Cox proportional hazards regression analysis was used in order to find risk factors for the recurrence. Using Kaplan-Meier survival analysis, the cumulative probability of survival rate considering recurrence as event of Adult group were 93.97% for one year, and maintained at 88.44% for two, three. four, and five years after surgery. In contrast, those of the Child group were 83.6%, 76.5%, 65.6%, 56.23%, and 40.16% for one, two, three, four, and five years after surgery, respectively. The Adult group had a better event-free survival curve than the Child group as analyzed by a Log-rank test (p = 0.020). According to multivariate weighted Cox regression analysis, the younger age at operation and the larger preoperative angle were significant risk factors for recurrence.