Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

During pregnancy, changes occur to influence the maternal gut microbiome, and potentially the fetal microbiome. Diet has been shown to impact the gut microbiome. Little research has been conducted examining diet during pregnancy with respect to the gut microbiome. To meet inclusion criteria, dietary analyses must have been conducted as part of the primary aim. The primary outcome was the composition of the gut microbiome (infant or maternal), as assessed using culture-independent sequencing techniques. This review identified seven studies for inclusion, five examining the maternal gut microbiome and two examining the fetal gut microbiome. Microbial data were attained through analysis of stool samples by 16S ribosomal RNA gene-based microbiota assessment. Studies found an association between the maternal diet and gut microbiome. High-fat diets (% fat of total energy), fat-soluble vitamins (mg/d) and fibre (g/d) were the most significant nutrients associated with the gut microbiota composition of both neonates and mothers. High-fat diets were significantly associated with a reduction in microbial diversity. High-fat diets may reduce microbial diversity, while fibre intake may be positively associated with microbial diversity. The results of this review must be interpreted with caution. The number of studies was low, and the risk of observational bias and heterogeneity across the studies must be considered. However, these results show promise for dietary intervention and microbial manipulation in order to favour an increase of health-associated taxa in the gut of the mother and her offspring.

The present study examined whether the combination of medium-chain TAG (MCT) along with exercise suppresses energy intake to a greater extent compared with either intervention alone. Twelve participants consumed a porridge breakfast containing 692·9 kJ of either vegetable or MCT oil on two separate occasions: one followed by rest for 240 min and another followed by rest broken up with 1 h of cycling at 65 % $\dot V$O2peak starting at 120 min. At 240 min, participants consumed a buffet lunch to satiation and recorded their food intake for the rest of the day. Expired air samples (for calculation of energy expenditure (EE)) and subjective ratings of appetite on visual analogue scales were taken every 30 min, and gastric emptying (GE) breath samples were taken every 15 min. No effect of either breakfast or exercise condition was observed on energy intake at any time point (P > 0·05) or no effect was observed on subjective appetite ratings (P > 0·05). Exercise trials resulted in significantly higher EE compared with resting trials (2960·6 kJ, 95 % CI 2528·9, 3392·2; P < 0·001), and MCT increased resting EE over 4 h compared with long-chain TAG (LCT) (124·8 kJ, 95 % CI 13·5, 236·0; P = 0·031). GE was accelerated by exercise, regardless of the breakfast consumed, but delayed by MCT in both resting and exercise trials. The results show that exercise causes energy deficits via increased EE without promoting dietary compensation. MCT has no effect on energy intake or satiety but increases EE under resting conditions. There is no additive effect of MCT and exercise on EE, intake or appetite ratings.

We recently reported an association of offspring educational attainment with polygenic risk scores (PRS) computed on parent’s non-transmitted alleles for educational attainment using the second GWAS meta-analysis article on educational attainment published by the Social Science Genetic Association Consortium. Here we test the replication of these findings using a more powerful PRS from the third GWAS meta-analysis article by the Consortium. Each of the key findings of our previous paper is replicated using this improved PRS (N = 2335 adolescent twins and their genotyped parents). The association of children’s attainment with their own PRS increased substantially with the standardized effect size, moving from β = 0.134, 95% CI = 0.079, 0.188 for EA2, to β = 0.223, 95% CI = 0.169, 0.278, p < .001, for EA3. Parent’s PRS again predicted the socioeconomic status (SES) they provided to their offspring and increased from β = 0.201, 95% CI = 0.147, 0.256 to β = 0.286, 95% CI = 0.239, 0.333. Importantly, the PRS for alleles not transmitted to their offspring — therefore acting via the parenting environment — was increased in effect size from β = 0.058, 95% CI = 0.003, 0.114 to β = 0.067, 95% CI = 0.012, 0.122, p = .016. As previously found, this non-transmitted genetic effect was fully accounted for by parental SES. The findings reinforce the conclusion that genetic effects of parenting are substantial, explain approximately one-third the magnitude of an individual’s own genetic inheritance and are mediated by parental socioeconomic competence.

Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (β = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (β = 0.20), and parental SES and offspring EA were significantly associated (β = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.

It is now generally recognised that liquid hydrogen offers a considerable increase in vehicle performance over the more conventional fuels, despite its relatively low density.

A design study on an upper stage, which uses a liquid hydrogen/ liquid oxygen chemical propulsion system, revealed a number of problem areas which extend beyond the current levels of experience and knowledge in rocket technology existing in the U.K. This study was made on the third stage of a communication satellite launching vehicle, and a number of the problems high-lighted during the course of the investigation, covering both the propulsion system and the structure, are described and discussed in terms of their importance and their effects on the launcher system. Solutions are suggested where possible—although, lacking practical confirmation, these must be tentative in the circumstances.

While no fundamental difficulties are anticipated in the development of a rocket engine using hydrogen, it is essential to accumulate some background of data and experience to ensure that early policy and designs are sound; the importance of beginning practical work as soon as possible is emphasised.

Internalizing symptoms during adolescence and beyond is a major public health concern, particularly because severe symptoms can lead to the diagnosis of a number of serious psychiatric conditions. This study utilizes a unique sample with a complex statistical method in order to explore Gene × Environment interactions found in internalizing symptoms during adolescence. Data for this study were drawn from a longitudinal prevention intervention study (n = 798) of Baltimore city school children. Internalizing symptom data were collected using self-report and blood or saliva samples genotyped using Affymetrix 6.0 microarrays. A major depression polygenic score was created for each individual using information from the major depressive disorder Psychiatric Genetics Consortium and used as a predictor in a latent trait–state–occasion model. The major depressive disorder polygenic score was a significant predictor of the stable latent trait variable, which captures time-independent phenotypic variability. In addition, an early childhood stressor of death or divorce was a significant predictor of occasion-specific variables. A Gene × Environment interaction was not a significant predictor of the latent trait or occasion variables. These findings support the importance of genetics on the stable latent trait portion of internalizing symptoms across adolescence.

The present study examines the interaction between a polygenic score and an elementary school-based universal preventive intervention trial. The polygenic score reflects the contribution of multiple genes and has been shown in prior research to be predictive of smoking cessation and tobacco use (Uhl et al., 2014). Using data from a longitudinal preventive intervention study, we examined age of first tobacco use from sixth grade to age 18. Genetic data were collected during emerging adulthood and were genotyped using the Affymetrix 6.0 microarray. The polygenic score was computed using these data. Discrete-time survival analysis was employed to test for intervention main and interaction effects with the polygenic score. We found a main effect of the intervention, with the intervention participants reporting their first cigarette smoked at an age significantly later than controls. We also found an Intervention × Polygenic Score interaction, with participants at the higher end of the polygenic score benefitting the most from the intervention in terms of delayed age of first use. These results are consistent with Belsky and colleagues' (e.g., Belsky, Bakermans-Kranenburg, & van IJzendoorn, 2007; Belsky & Pleuss, 2009, 2013; Ellis, Boyce, Belsky, Bakermans-Kranenburg, & van IJzendoorn, 2011) differential susceptibility hypothesis and the concept of “for better or worse,” wherein the expression of genetic variants are optimally realized in the context of an enriched environment, such as provided by a preventive intervention.

This paper describes the system architecture of a newly constructed radio telescope – the Boolardy engineering test array, which is a prototype of the Australian square kilometre array pathfinder telescope. Phased array feed technology is used to form multiple simultaneous beams per antenna, providing astronomers with unprecedented survey speed. The test array described here is a six-antenna interferometer, fitted with prototype signal processing hardware capable of forming at least nine dual-polarisation beams simultaneously, allowing several square degrees to be imaged in a single pointed observation. The main purpose of the test array is to develop beamforming and wide-field calibration methods for use with the full telescope, but it will also be capable of limited early science demonstrations.

In this article we present the protocol of the Birmingham Registry for Twin Heritability Studies (BiRTHS), which aims to establish a long-term prospective twin registry with twins identified from the antenatal period and subjected to detailed follow-up. We plan to investigate the concordance in anthropo-metrics and early childhood phenotypes between 66 monozygotic and 154 dizygotic twin pairs in the first 2 years of recruitment. In this project we plan to determine the relative contributions of heritability and environment to fetal growth, birth size, growth in infancy and development up to 2 years of age in an ethnically mixed population. Twins will be assessed with the Griffitth's Mental Development Scales, which will enable us to obtain detailed information on development. As maternal depression may have an effect on the twins' neurodevelopment, the Edinburgh Postnatal Depression Scale will be used at various stages during pregnancy and after delivery to assess maternal depressive symptoms. The increasing prevalence of obesity in both adults and children has raised concerns about the effect of maternal obesity in pregnancy on fetal growth. The prospective study design gives us the opportunity to obtain data on maternal nutrition (reflected by body mass index) and ante- and postnatal growth and development of twins.

This article is an updated review of the Pittsburgh Registry of Infant Multiplets including recruitment methods, data collection, and results of pilot studies conducted in this registry. The main goal of the registry is to study psychological development. The risk for behavior disorders including substance use disorders, as well as language development and dental health are among research targets. Pilot data on the heritability of minor physical anomalies and neuropsychological characteristics (Continuous Performance Test) are reported.