Infant Neuromotor Development and Neuropsychiatric Problems Modern Epidemiological approaches

__Background:__ This thesis focuses on the role of infant neuromotor development in relation to neuropsychiatric problems. I performed genetic studies to further our understanding of the association between neuromotor development in infancy and behavioral problems in childhood. Methods: Studies described in this thesis were performed in Generation R, a large prospective population-based cohort in Rotterdam, the Netherlands. In a large ample of children at age 9-20 weeks, 15 research assistants assessed neuromotor development (tone, responses, senses and other observations) using Touwen instrument. Parents reported on their behavior during childhood and cognitive abilities were observed at age 6 years. __Objectives:__ The aims of this thesis were 1) to study the associations between neuromotor development during infancy and childhood behavior and cognitive functioning, 2) to examine the extend to which genetic susceptibility for psychiatric disorders influences neuromotor development 3) to understand the role of infant neuromotor development in the association of genetic susceptibility for psychiatric disorders with behavioral outcomes during childhood. __Results:__ I showed that infant neuromotor development is associated with shifting and cold, but not hot executive functioning, as well as with autistic symptoms. I further found that infant neuromotor development (low muscle tone and senses) predicts internalizing, but not externalizing symptoms during childhood. Problems in shifting partly mediated association between low muscle tone and later internalizing symptoms. Furthermore, a higher genetic risk for schizophrenia and a lower genetic risk for bipolar disorder was associated with non-optimal overall neuromotor development during infancy. I also found that the genetic risk for autism spectrum disorder (ASD) predicts non-optimal neuromotor development and in particular low muscle tone, while the genetic risk for attention-deficit/hyperactivity disorder (ADHD) predicts non-optimal senses and other observations in boys. Infant neuromotor development mediates the association of genetic risk for ASD and ADHD with autistic symptoms. In particular, low muscle tone mediates the association of genetic risk for ASD with autistic symptoms, while senses and other observations mediate association of genetic risk for ASD and ADHD with autistic symptoms. __Conclusion:__ Early identification of non-optimal neuromotor development in infants with a high genetic risk, followed by early intervention, could potentially reduce autistic symptoms in children

Prevention and Management of Type 2 Diabetes and Metabolic Syndrome in the Time of COVID-19: Should We Add a Cup of Coffee?

Recent evidence shows that COVID-19 patients with existing metabolic disorders, such as diabetes and metabolic syndrome, are exposed to a high risk of morbidity and mortality. At the same time, in order to manage the pandemic, the health authorities around the world are advising people to stay at home. This results in decreased physical activity and an increased consumption of an unhealthy diet, which often leads to an increase in body weight, risk for diabetes, insulin resistance, and metabolic syndrome, and thus, paradoxically, to a high risk of morbidity and mortality due to COVID-19 complications. Here we summarize the evidence demonstrating that the promotion of a healthy life style, including physical activity and a dietary intake of natural polyphenols present in coffee and tea, has the potential to improve the prevention and management of insulin resistance and diabetes in the time of COVID-19 pandemic. Particularly, it would be pertinent to evaluate further the potential positive effects of coffee beverages, rich in natural polyphenols, as an adjuvant therapy for COVID-19, which appear not to be studied sufficiently

Effects of Pre- and Postnatal Early-Life Stress on Internalizing, Adiposity, and Their Comorbidity

Objective: Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions. Method: Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity. Results: Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (β [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity. Conclusion: We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time. Diversity &amp; Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group.</p

SARS-CoV-2 virus outbreak and the emergency public health measures in Bosnia and Herzegovina: January – july 2020

Between March 5th and July 25th, 2020, the total number of SARS-CoV-2 confirmed cases in Bosnia and Herzegovina (BH) was 10,090, corresponding to a cumulative incidence rate of 285.7/100,000 population. Demographic and clinical information on all the cases along with exposure and contact information were collected using a standardized case report form. In suspected SARS-CoV-2 cases, respiratory specimens were collected and tested by real-time reverse-transcriptase polymerase chain reaction assay. The dynamic of the outbreak was summarized using epidemiolog

DNA Methylation at Birth and Fine Motor Ability in Childhood:An Epigenome-wide Association Study with Replication

Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.The EWAS data was funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and a grant from the National Institute of Child and Human Development (R01HD068437). HT was supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). FS was supported by a Royal Netherlands Academy of Science and Art (KNAW) Van Leersum fellowship. ML is supported by the scholarship from the China Scholarship Council (201706990036). CC is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements No 101039672 (TEMPO) and No 848158 (EarlyCause). This project received funding from the European Union’s Horizon 2020 research and innovation programme (733206, LifeCycle).The epigenetic studies in INMA were mainly funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, CP18/00018), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615) Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn)

The complex role of parental separation in the association between family conflict and child problem behavior

Parental separation is a major adverse childhood experience. Parental separation is generally preceded by conflict, which is itself a risk factor for child problem behavior. Whether parental separation independent of conflict has negative effects on child problem behavior is unclear. This study was embedded in Generation R, a population-based cohort followed from fetal life until age 9 years. Information on family conflict was obtained from 5,808 mothers and fathers. The 4-way decomposition method was used to apportion the effects of prenatal family conflict and parental separation on child problem behavior into 4 nonoverlapping components. Structural equation modeling was used to test bidirectional effects of child problem behavior and family conflict over time. Family conflict from pregnancy onward and parental separation each strongly predicted child problem behavior up to preadolescence according to maternal and paternal ratings. Using the 4-way decomposition method, we found evidence for a strong direct effect of prenatal family conflict on child problem behavior, for reference interaction, and for mediated interaction. The evidence for interaction implies that prenatal family conflict increased the children’s vulnerability to the harmful effect of parental separation. There was no evidence of a pure indirect effect of parental separation on child problem behavior. Overall, results indicated that if parental separation occurs in families with low levels of conflict, parental separation does not predict more child problem behavior. Moreover, the bidirectional pattern suggested that child problem behavior influences the persistence of family conflic

Polygenic Risk Scores for Developmental Disorders, Neuromotor Functioning During Infancy, and Autistic Traits in Childhood

Background: Impaired neuromotor development is often one of the earliest observations in children with autism spectrum disorder (ASD). We investigated whether a genetic predisposition to developmental disorders was associated with nonoptimal neuromotor development during infancy and examined the genetic correlation between nonoptimal neuromotor development and autistic traits in the general population. Methods: In a population-based cohort in The Netherlands (2002–2006), we calculated polygenic risk scores (PRSs) for ASD and attention-deficit/hyperactivity disorder (ADHD) using genome-wide association study summary statistics. In 1921 children with genetic data, parents rated autistic traits at 6 years of age. Among them, 1174 children (61.1%) underwent neuromotor examinations (tone, responses, senses, and other observations) during infancy (9–20 weeks of age). We used linear regressions to examine associations of PRSs with neuromotor scores and autistic traits. We performed a bivariate genome-based restricted maximum likelihood analysis to explore whether genetic susceptibility underlies the association between neuromotor development and autistic traits. Results: Higher PRSs for ASD were associated with less optimal overall infant neuromotor development, in particular low muscle tone. Higher PRSs for ADHD were associated with less optimal senses. PRSs for ASD and those for ADHD both were associated with autistic traits. The single nucleotide polymorphism–based heritability of overall motor development was 20% (SE = .21) and of autistic traits was 68% (SE = .26). The genetic correlation between overall motor development and autistic traits was .35 (SE = .21, p < .001). Conclusions: We found that genetic liabilities for ASD and ADHD covary with neuromotor development during infancy. Shared genetic liability might partly explain the association between nonoptimal neuromotor development during infancy and autistic traits in childhood

Preschool family irregularity and the development of sleep problems in childhood

Background: Previous studies have shown that poor family environments are related to more sleep problems; however, little is known about how family irregularity in early life affects the development of sleep problems ove

Higher circulating cortisol in the follicular vs. Luteal phase of the menstrual cycle: A meta-analysis

Although results of animal research show that interactions between stress and sex hormones are implicated in the development of affective disorders in women, translation of these findings to patients has been scarce. As a basic step toward advancing this field of research, we analyzed findings of studies which reported circulating cortisol levels in healthy women in the follicular vs. luteal phase of the menstrual cycle. We deemed this analysis critical not only to advance our understanding of basic physiology, but also as an important contrast to the findings of future studies evaluating stress and sex hormones in women with affective disorders. We hypothesized that cortisol levels would be lower in the follicular phase based on the proposition that changes in levels of potent GABAergic neurosteroids, including allopregnanolone, during the menstrual cycle dynamically change in the opposite direction relative to cortisol levels. Implementing strict inclusion criteria, we compiled results of high-quality studies involving 778 study participants to derive a standardized mean difference between circulating cortisol levels in the follicular vs. luteal phase of the menstrual cycle. In line with our hypothesis, our meta-analysis found that women in the follicular phase had higher cortisol levels than women in the luteal phase, with an overall Hedges’ g of 0.13 (p < 0.01) for the random effects model. No significant between-study difference was detected, with the level of heterogeneity in the small range. Furthermore, there was no evidence of publication bias. As cortisol regulation is a delicate process, we review some of the basic mechanisms by which progesterone, its potent metabolites, and estradiol regulate cortisol output and circulation to contribute to the net effect of higher cortisol in the follicular phase