Relationship between Birth Weight, Early Growth Rate, and Body Composition in 5- to 7-Year-Old Children

Background: Programing of body composition during intrauterine growth may contribute to the higher risk for cardio-metabolic disease in individuals born small or large for gestational age (SGA, LGA). Compensations of intrauterine growth by catch-up or catch-down postnatal growth may lead to adverse consequences like a thin-fat phenotype. Methods: The impact of (i) birth weight as well as (ii) the interaction between birth weight and catch-up or catch-down growth during the first 2 years of life on fat-free mass index (FFMI) and fat mass index (FMI) in 3,204 5–7-year-old children were investigated using Hattori’s body composition chart. Body composition results were compared to appropriate for gestational age (AGA) birth weight with the same body mass index (BMI). Results: In total, 299 children at age 5–7 years were categorized as SGA, 2,583 as AGA, and 322 as LGA. When compared to AGA-children, BMI at 5–7 years of age was higher in LGA-children (15.5 vs. 16.2 kg/m2; p < 0.001) but not different in SGA-children. Compared to AGA with the same BMI, LGA was associated with higher FMI and a lower FFMI in 5–7-year-old girls. This phenotype was also seen for both sexes with catch-down growth during the first 2 years of life whereas catch-up growth prevented the higher FMI and lower FFMI per BMI. By contrast, SGA was associated with a higher FFMI and lower FMI in 5–7-year-old boys compared to AGA boys with the same BMI. This phenotype was also seen with catch-down growth in both genders whereas catch-up growth in girls led to more gain in FMI per BMI. Conclusion: LGA with a compensatory catch-down postnatal growth may be a risk factor for the development of disproportionate gain in fat over lean mass whereas SGA with a catch-down postnatal growth seems to favor the subsequent accretion of lean over fat mass. A higher propensity of lean mass accretion during postnatal growth in boys compared to girls explains sex differences in these phenotypes

Navigieren

Prof. Dr. Jens Schröter, Christoph Borbach, Max Kanderske und Prof. Dr. Benjamin Beil sind Herausgeber der Reihe. Die Herausgeber*innen der einzelnen Hefte sind renommierte Wissenschaftler*innen aus dem In- und Ausland.Navigieren ist längst kein Unikum professionalisierter Seefahrer:innen mehr, sondern als Smartphone- und Browser-Praktik fester Bestandteil des vernetzten digitalen Alltags. Da Wegfindungen durch On- und Offline-Räume navigationsspezifische Formen von Medienkompetenz voraussetzen und hervorbringen, fordern sie die Intensivierung der medienkulturwissenschaftlichen Beschäftigung mit den situierten und technisierten Medienpraktiken der Navigation geradezu heraus. Die Ausgabe nimmt diesen Befund zum Anlass, polyperspektivische Zugänge zum »Navigieren« vorzustellen. Die körper-, kultur- und medientechnischen Facetten des Navigierens stehen dabei ebenso im Fokus wie ihre historischen Ausgestaltungen, die Arbeit am und im Datenmaterial von Navigationsmedien und die Theoretisierung postdigitaler Sensor-Medien-Kulturen, die dem Umstand Rechnung trägt, dass es nicht allein Daten, Dinge und Körper sind, die es zu navigieren gilt, sondern zunehmend nicht-menschliche Akteure selbst zielgerichtete Raumdurchquerungen praktizieren. Fehlte es in der (deutschsprachigen) Medienkulturwissenschaft bislang an einer Bündelung heterogener navigationsspezifischer Forschungsarbeiten, gibt diese Ausgabe einen Überblick über das Feld, seine Forscher:innen und Fragestellungen. Denn trotz des Spatial Turns in den Humanities und der gegenwärtigen Konjunktur geomedialer Arbeiten, scheint die synthetisierende Fokussierung auf Medien und Praktiken des Navigierens in historischer, ethnografischer, technischer und theoretischer Perspektive bislang ein Desiderat darzustellen.Navigation is no longer unique to the context of professional seafaring, but has become an integral part of networked digital everyday life enabled through smartphones and web browsers. Indeed, finding one’s way through online and offline spaces increasingly presupposes and produces specific forms of media competence one could call »navigational«. In this, a ›media cultural studies‹ perspective on the situated and ›technologized‹ media practices of navigation becomes imperative to understanding the contemporary media landscape. Issue 1/22 of Navigationen answers this call by presenting polyperspectival approaches to »navigating«. The contributions discuss the bodily, cultural, and media-technical facets of navigation, as well as its historical forms, the work on and in the data produced by and with navigational media, and the theorization of post-digital ›sensor media cultures‹. In doing so, the issue acknowledges that not only do data, things, and bodies need to be ›navigated‹ in the context of logistics, but that the increasingly autonomous wayfinding processes of non-human actors change the notion of navigation itself. As (German language) media cultural studies has so far lacked a convincing compilation of heterogeneous approaches to studying navigation, this issue provides an overview of the field, its researchers and questions. Despite the spatial turn in the humanities and a recent surge in geomedia studies, an approach towards the media and practices of navigation that combines historical, ethnographic, technical and theoretical perspectives, has remained a desideratum until now. The issue fills this gap

Rare Copy Number Variants in \u3cem\u3eNRXN1\u3c/em\u3e and \u3cem\u3eCNTN6\u3c/em\u3e Increase Risk for Tourette Syndrome

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (\u3c 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (\u3e 1 Mb), singleton events (OR = 2.28, 95% CI [1.39–3.79], p = 1.2 × 10−3) and known, pathogenic CNVs (OR = 3.03 [1.85–5.07], p = 1.5 × 10−5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6–156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS

Current Guidelines for Obesity Prevention in Childhood and Adolescence

Objective: Current guidelines for prevention of obesity in childhood and adolescence are discussed. Methods: A literature search was performed in Medline via PubMed, and appropriate studies were analyzed. Results: Programs to prevent childhood obesity have so far remained mainly school-based and effects have been limited. Analyses by age group show that prevention programs have the best results in younger children (Conclusion: Behavior-oriented prevention programs showed only limited long-term effects. Certain groups at risk for the development of obesity are not reached effectively by current programs. Although universally valid conclusions cannot be drawn given the heterogeneity of available studies, clearly combining behavior-based programs with community-based prevention to counteract an ‘obesogenic environment' is crucial for sustainable success of future obesity prevention programs

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe