Content, diagnostic, correlational, and genetic similarities between common measures of childhood aggressive behaviors and related psychiatric traits.

BACKGROUND: Given the role of childhood aggressive behavior (AGG) in everyday child development, precise and accurate measurement is critical in clinical practice and research. This study aims to quantify agreement among widely used measures of childhood AGG regarding item content, clinical concordance, correlation, and underlying genetic construct. METHODS: We analyzed data from 1254 Dutch twin pairs (age 8-10 years, 51.1% boys) from a general population sample for whom both parents completed the A-TAC, CBCL, and SDQ at the same occasion. RESULTS: There was substantial variation in item content among AGG measures, ranging from .00 (i.e., mutually exclusive) to .50 (moderate agreement). Clinical concordance (i.e., do the same children score above a clinical threshold among AGG measures) was very weak to moderate with estimates ranging between .01 and .43 for mother-reports and between .12 and .42 for father-reports. Correlations among scales were weak to strong, ranging from .32 to .70 for mother-reports and from .32 to .64 for father-reports. We found weak to very strong genetic correlations among the measures, with estimates between .65 and .84 for mother-reports and between .30 and .87 for father-reports. CONCLUSIONS: Our results demonstrated that degree of agreement between measures of AGG depends on the type (i.e., item content, clinical concordance, correlation, genetic correlation) of agreement considered. Because agreement was higher for correlations compared to clinical concordance (i.e., above or below a clinical cutoff), we propose the use of continuous scores to assess AGG, especially for combining data with different measures. Although item content can be different and agreement among observed measures may not be high, the genetic correlations indicate that the underlying genetic liability for childhood AGG is consistent across measures.

Harmonizing behavioral outcomes across studies, raters, and countries: application to the genetic analysis of aggression in the ACTION Consortium.

BACKGROUND: Aggression in children has genetic and environmental causes. Studies of aggression can pool existing datasets to include more complex models of social effects. Such analyses require large datasets with harmonized outcome measures. Here, we made use of a reference panel for phenotype data to harmonize multiple aggression measures in school-aged children to jointly analyze data from five large twin cohorts. METHODS: Individual level aggression data on 86,559 children (42,468 twin pairs) were available in five European twin cohorts measured by different instruments. A phenotypic reference panel was collected which enabled a model-based phenotype harmonization approach. A bi-factor integration model in the integrative data analysis framework was developed to model aggression across studies while adjusting for rater, age, and sex. Finally, harmonized aggression scores were analyzed to estimate contributions of genes, environment, and social interaction to aggression. The large sample size allowed adequate power to test for sibling interaction effects, with unique dynamics permitted for opposite-sex twins. RESULTS: The best-fitting model found a high level of overall heritability of aggression (~60%). Different heritability rates of aggression across sex were marginally significant, with heritability estimates in boys of ~64% and ~58% in girls. Sibling interaction effects were only significant in the opposite-sex twin pairs: the interaction effect of males on their female co-twin differed from the effect of females on their male co-twin. An aggressive female had a positive effect on male co-twin aggression, whereas more aggression in males had a negative influence on a female co-twin. CONCLUSIONS: Opposite-sex twins displayed unique social dynamics of aggressive behaviors in a joint analysis of a large, multinational dataset. The integrative data analysis framework, applied in combination with a reference panel, has the potential to elucidate broad, generalizable results in the investigation of common psychological traits in children.

Genetics and Not Shared Environment Explains Familial Resemblance in Adult Metabolomics Data.

Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.

[Haemorrhagic shock after frenotomy of the lingual and maxillary labial frenula in a neonate]. / Hemorragische shock na frenulotomie bij een neonaat.

Frenotomy of the lingual and maxillary labial frenula in neonates is considered a safe procedure and is increasingly performed globally. However, there is no consistent evidence for the indication and effectiveness of this intervention. In this clinical lesson, we show that frenotomy of the lingual and maxillary labial frenula in neonates is controversial and can have serious complications. We describe a patient that, in addition to pain and the risk of infection, was in a life-threatening haemorrhagic shock after frenotomy of the lingual and maxillary labial frenula. Frenotomy should only be considered after a multi-disciplinary approach of neonates with breastfeeding problems in whom a medical cause is excluded and no contraindications have been identified.

Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation.

Channelling of glucose via glycogen, known as the glycogen shunt, may play an important role in the metabolism of brain tumours, especially in hypoxic conditions. We aimed to dissect the role of glycogen degradation in glioblastoma (GBM) response to ionising radiation (IR). Knockdown of the glycogen phosphorylase liver isoform (PYGL), but not the brain isoform (PYGB), decreased clonogenic growth and survival of GBM cell lines and sensitised them to IR doses of 10-12 Gy. Two to five days after IR exposure of PYGL knockdown GBM cells, mitotic catastrophy and a giant multinucleated cell morphology with senescence-like phenotype developed. The basal levels of the lysosomal enzyme alpha-acid glucosidase (GAA), essential for autolysosomal glycogen degradation, and the lipidated forms of gamma-aminobutyric acid receptor-associated protein-like (GABARAPL1 and GABARAPL2) increased in shPYGL U87MG cells, suggesting a compensatory mechanism of glycogen degradation. In response to IR, dysregulation of autophagy was shown by accumulation of the p62 and the lipidated form of GABARAPL1 and GABARAPL2 in shPYGL U87MG cells. IR increased the mitochondrial mass and the colocalisation of mitochondria with lysosomes in shPYGL cells, thereby indicating reduced mitophagy. These changes coincided with increased phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase 2, slower ATP generation in response to glucose loading and progressive loss of oxidative phosphorylation. The resulting metabolic deficiencies affected the availability of ATP required for mitosis, resulting in the mitotic catastrophy observed in shPYGL cells following IR. PYGL mRNA and protein levels were higher in human GBM than in normal human brain tissues and high PYGL mRNA expression in GBM correlated with poor patient survival. In conclusion, we show a major new role for glycogen metabolism in GBM cancer. Inhibition of glycogen degradation sensitises GBM cells to high-dose IR indicating that PYGL is a potential novel target for the treatment of GBMs.

18F-FDG PET/CT Scans Can Identify Sub-Groups of NSCLC Patients with High Glucose Uptake in the Majority of Their Tumor Lesions.

Background: Reprogrammed glucose metabolism is a hallmark of cancer making it an attractive therapeutic target, especially in cancers with high glucose uptake such as non-small cell lung cancer (NSCLC). Tools to select patients with high glucose uptake in the majority of tumor lesions are essential in the development of anti-cancer drugs targeting glucose metabolism. Type 2 diabetes mellitus (T2DM) patients may have tumors highly dependent on glucose uptake. Surprisingly, this has not been systematically studied. Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) scans. Methods: Routine primary diagnostic 18F-FDG PET/CT scans of consecutive NSCLC patients were included. Mean standardized uptake value (SUVmean) of 18F-FDG was determined for all evaluable tumor lesions and corrected for serum glucose levels according to the European Association of Nuclear Medicine Research Ltd guidelines. Patient characteristics potentially determining degree of tumor lesion glucose uptake in the majority of tumor lesions per patient were investigated. Results: The cohort consisted of 102 patients, 28 with T2DM and 74 without T2DM. The median SUVmean per patient ranged from 0.8 to 35.2 (median 4.2). T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, P < 0.001 and SUVmean 5.4 vs 3.7, P = 0.009, respectively). However, in multivariable analysis, high tumor lesion glucose uptake was only independently determined by number of tumor lesions ≥1 mL per patient (odds ratio 0.8, 95% confidence interval 0.7-0.9). Conclusions: 18F-FDG PET/CT scans can identify sub-groups of NSCLC patients with high glucose uptake in the majority of their tumor lesions. T2DM patients had higher tumor lesion glucose uptake than non-diabetic patients. However, this was not independent of other factors such as the histological subtype and number of tumor lesions per patient.

The role of local therapy in the treatment of solitary melanoma progression on immune checkpoint inhibition: A multicentre retrospective analysis.

INTRODUCTION: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma. PATIENTS AND METHODS: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation. RESULTS: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences. CONCLUSION: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes.

Sulfonylurea derivatives and cancer, friend or foe?

Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.

Data Integration Methods for Phenotype Harmonization in Multi-Cohort Genome-Wide Association Studies With Behavioral Outcomes.

Parallel meta-analysis is a popular approach for increasing the power to detect genetic effects in genome-wide association studies across multiple cohorts. Consortia studying the genetics of behavioral phenotypes are oftentimes faced with systematic differences in phenotype measurement across cohorts, introducing heterogeneity into the meta-analysis and reducing statistical power. This study investigated integrative data analysis (IDA) as an approach for jointly modeling the phenotype across multiple datasets. We put forth a bi-factor integration model (BFIM) that provides a single common phenotype score and accounts for sources of study-specific variability in the phenotype. In order to capitalize on this modeling strategy, a phenotype reference panel was utilized as a supplemental sample with complete data on all behavioral measures. A simulation study showed that a mega-analysis of genetic variant effects in a BFIM were more powerful than meta-analysis of genetic effects on a cohort-specific sum score of items. Saving the factor scores from the BFIM and using those as the outcome in meta-analysis was also more powerful than the sum score in most simulation conditions, but a small degree of bias was introduced by this approach. The reference panel was necessary to realize these power gains. An empirical demonstration used the BFIM to harmonize aggression scores in 9-year old children across the Netherlands Twin Register and the Child and Adolescent Twin Study in Sweden, providing a template for application of the BFIM to a range of different phenotypes. A supplemental data collection in the Netherlands Twin Register served as a reference panel for phenotype modeling across both cohorts. Our results indicate that model-based harmonization for the study of complex traits is a useful step within genetic consortia.

The Relationship between Family Violence and Self-Control in Adolescence: A Multi-Level Meta-Analysis.

Theoretical studies propose an association between family violence and low self-control in adolescence; however, empirical findings of this association are inconclusive. The aim of the present research was to systematically summarize available findings on the relation between family violence and self-control across adolescence. We included 28 studies with 143 effect sizes, representing more than 25,000 participants of eight countries from early to late adolescence. Applying a three-level meta-analysis, taking dependency between effect sizes into account while retaining statistical power, we examined the magnitude and direction of the overall effect size. Additionally, we investigated whether theoretical moderators (e.g., age, gender, country), and methodological moderators (e.g., time lag between family violence and self-control, informant) influenced the magnitude of the association between family violence and self-control. Our results revealed that family violence and self-control have a small to moderate significant negative association (r = -0.191). This association did not vary across gender, country, and informants. The strength of the association, however, decreased with age and in longitudinal studies. This finding provides evidence that researchers and clinicians may expect low self-control in the wake of family violence, especially in early adolescence. Recommendations for future research in the area are discussed.