Wellbeing and brain structure: A comprehensive phenotypic and genetic study of image-derived phenotypes in the UK Biobank

Wellbeing, an important component of mental health, is influenced by genetic and environmental factors. Previous association studies between brain structure and wellbeing have typically focused on volumetric measures and employed small cohorts. Using the UK Biobank Resource, we explored the relationships between wellbeing and brain morphometrics (volume, thickness and surface area) at both phenotypic and genetic levels. The sample comprised 38,982 participants with neuroimaging and wellbeing phenotype data, of which 19,234 had genotypes from which wellbeing polygenic scores (PGS) were calculated. We examined the association of wellbeing phenotype and PGS with all brain regions (including cortical, subcortical, brainstem and cerebellar regions) using multiple linear models, including (1) basic neuroimaging covariates and (2) additional demographic factors that may synergistically impact wellbeing and its neural correlates. Genetic correlations between genomic variants influencing wellbeing and brain structure were also investigated. Small but significant associations between wellbeing and volumes of several cerebellar structures (β = 0.015–0.029, PFDR = 0.007–3.8 × 10−9), brainstem, nucleus accumbens and caudate were found. Cortical associations with wellbeing included volume of right lateral occipital, thickness of bilateral lateral occipital and cuneus, and surface area of left superior parietal, supramarginal and pre-/post-central regions. Wellbeing-PGS was associated with cerebellar volumes and supramarginal surface area. Small mediation effects of wellbeing phenotype and PGS on right VIIIb cerebellum were evident. No genetic correlation was found between wellbeing and brain morphometric measures. We provide a comprehensive overview of wellbeing-related brain morphometric variation. Notably, small effect sizes reflect the multifaceted nature of this concept

Siblings of children with life-limiting conditions: psychological adjustment and sibling relationships

BACKGROUND: This study explored psychological adjustment and sibling relationships of siblings of children with life‐limiting conditions (LLCs), expanding on previous research by defining LLCs using a systematic classification of these conditions. METHODS: Thirty‐nine siblings participated, aged 3–16 years. Parents completed measures of siblings' emotional and behavioural difficulties, quality of life, sibling relationships and impact on families and siblings. Sibling and family adjustment and relationships were compared with population norms, where available, and to a matched comparison group of siblings of children with autistic spectrum disorder (ASD), as a comparable ‘high risk’ group. RESULTS: LLC siblings presented significantly higher levels of emotional and behavioural difficulties, and lower quality of life than population norms. Their difficulties were at levels comparable to siblings of children with ASD. A wider impact on the family was confirmed. Family socio‐economic position, time since diagnosis, employment and accessing hospice care were factors associated with better psychological adjustment. CONCLUSIONS: Using a systematic classification of LLCs, the study supported earlier findings of increased levels of psychological difficulties in siblings of children with a LLC. The evidence is (i) highlighting the need to provide support to these siblings and their families, and (ii) that intervention approaches could be drawn from the ASD field

Genetic and environment effects on structural neuroimaging endophenotype for bipolar disorder: a novel molecular approach

We investigated gene–environment effects on structural brain endophenotype in bipolar disorder (BD) using a novel method of combining polygenic risk scores with epigenetic signatures since traditional methods of examining the family history and trauma effects have significant limitations. The study enrolled 119 subjects, including 55 BD spectrum (BDS) subjects diagnosed with BD or major depressive disorder (MDD) with subthreshold BD symptoms and 64 non-BDS subjects comprising 32 MDD subjects without BD symptoms and 32 healthy subjects. The blood samples underwent genome-wide genotyping and methylation quantification. We derived polygenic risk score (PRS) and methylation profile score (MPS) as weighted summations of risk single nucleotide polymorphisms and methylation probes, respectively, which were considered as molecular measures of genetic and environmental risks for BD. Linear regression was used to relate PRS, MPS, and their interaction to 44 brain structure measures quantified from magnetic resonance imaging (MRI) on 47 BDS subjects, and the results were compared with those based on family history and childhood trauma. After multiplicity corrections using false discovery rate (FDR), MPS was found to be negatively associated with the volume of the medial geniculate thalamus (FDR = 0.059, partial R2 = 0.208). Family history, trauma scale, and PRS were not associated with any brain measures. PRS and MPS show significant interactions on whole putamen (FDR = 0.09, partial R2 = 0.337). No significant gene–environment interactions were identified for the family history and trauma scale. PRS and MPS generally explained greater proportions of variances of the brain measures (range of partial R2 = [0.008, 0.337]) than the clinical risk factors (range = [0.004, 0.228])

Stellar winds from Massive Stars

We review the various techniques through which wind properties of massive stars - O stars, AB supergiants, Luminous Blue Variables (LBVs), Wolf-Rayet (WR) stars and cool supergiants - are derived. The wind momentum-luminosity relation (e.g. Kudritzki et al. 1999) provides a method of predicting mass-loss rates of O stars and blue supergiants which is superior to previous parameterizations. Assuming the theoretical sqrt(Z) metallicity dependence, Magellanic Cloud O star mass-loss rates are typically matched to within a factor of two for various calibrations. Stellar winds from LBVs are typically denser and slower than equivalent B supergiants, with exceptional mass-loss rates during giant eruptions Mdot=10^-3 .. 10^-1 Mo/yr (Drissen et al. 2001). Recent mass-loss rates for Galactic WR stars indicate a downward revision of 2-4 relative to previous calibrations due to clumping (e.g. Schmutz 1997), although evidence for a metallicity dependence remains inconclusive (Crowther 2000). Mass-loss properties of luminous (> 10^5 Lo) yellow and red supergiants from alternative techniques remain highly contradictory. Recent Galactic and LMC results for RSG reveal a large scatter such that typical mass-loss rates lie in the range 10^-6 .. 10^-4 Mo/yr, with a few cases exhibiting 10^-3 Mo/yr.Comment: 16 pages, 2 figures, Review paper to appear in Proc `The influence of binaries on stellar population studies', Brussels, Aug 2000 (D. Vanbeveren ed.), Kluwe

Pilot study to test the feasibility of a trial design and complex intervention on PRIoritising MUltimedication in Multimorbidity in general practices (PRIMUMpilot).

Published onlineJournal ArticleThis is the final version of the article. Available from BMJ Publishing Group via the DOI in this record.OBJECTIVE: To improve medication appropriateness and adherence in elderly patients with multimorbidity, we developed a complex intervention involving general practitioners (GPs) and their healthcare assistants (HCA). In accordance with the Medical Research Council guidance on developing and evaluating complex interventions, we prepared for the main study by testing the feasibility of the intervention and study design in a cluster randomised pilot study. SETTING: 20 general practices in Hesse, Germany. PARTICIPANTS: 100 cognitively intact patients ≥65 years with ≥3 chronic conditions, ≥5 chronic prescriptions and capable of participating in telephone interviews; 94 patients completed the study. INTERVENTION: The HCA conducted a checklist-based interview with patients on medication-related problems and reconciled their medications. Assisted by a computerised decision-support system (CDSS), the GPs discussed medication intake with patients and adjusted their medication regimens. The control group continued with usual care. OUTCOME MEASURES: Feasibility of the intervention and required time were assessed for GPs, HCAs and patients using mixed methods (questionnaires, interviews and case vignettes after completion of the study). The feasibility of the study was assessed concerning success of achieving recruitment targets, balancing cluster sizes and minimising drop-out rates. Exploratory outcomes included the medication appropriateness index (MAI), quality of life, functional status and adherence-related measures. MAI was evaluated blinded to group assignment, and intra-rater/inter-rater reliability was assessed for a subsample of prescriptions. RESULTS: 10 practices were randomised and analysed per group. GPs/HCAs were satisfied with the interventions despite the time required (35/45 min/patient). In case vignettes, GPs/HCAs needed help using the CDSS. The study made no patients feel uneasy. Intra-rater/inter-rater reliability for MAI was excellent. Inclusion criteria were challenging and potentially inadequate, and should therefore be adjusted. Outcome measures on pain, functionality and self-reported adherence were unfeasible due to frequent missing values, an incorrect manual or potentially invalid results. CONCLUSIONS: Intervention and trial design were feasible. The pilot study revealed important limitations that influenced the design and conduct of the main study, thus highlighting the value of piloting complex interventions. TRIAL REGISTRATION NUMBER: ISRCTN99691973; Results.Funding has been provided by the German Federal Ministry of Education and Research, BMBF, grant number 01GK0702

Enteric dysbiosis and fecal calprotectin expression in premature infants.

BackgroundPremature infants often develop enteric dysbiosis with a preponderance of Gammaproteobacteria, which has been related to adverse clinical outcomes. We investigated the relationship between increasing fecal Gammaproteobacteria and mucosal inflammation, measured by fecal calprotectin (FC).MethodsStool samples were collected from very-low-birth weight (VLBW) infants at ≤2, 3, and 4 weeks' postnatal age. Fecal microbiome was surveyed using polymerase chain reaction amplification of the V4 region of 16S ribosomal RNA, and FC was measured by enzyme immunoassay.ResultsWe enrolled 45 VLBW infants (gestation 27.9 ± 2.2 weeks, birth weight 1126 ± 208 g) and obtained stool samples at 9.9 ± 3, 20.7 ± 4.1, and 29.4 ± 4.9 days. FC was positively correlated with the genus Klebsiella (r = 0.207, p = 0.034) and its dominant amplicon sequence variant (r = 0.290, p = 0.003), but not with the relative abundance of total Gammaproteobacteria. Klebsiella colonized the gut in two distinct patterns: some infants started with low Klebsiella abundance and gained these bacteria over time, whereas others began with very high Klebsiella abundance.ConclusionIn premature infants, FC correlated with relative abundance of a specific pathobiont, Klebsiella, and not with that of the class Gammaproteobacteria. These findings indicate a need to define dysbiosis at genera or higher levels of resolution

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag

A Genome-Wide Association Study of Neuroticism in a Population-Based Sample

Neuroticism is a moderately heritable personality trait considered to be a risk factor for developing major depression, anxiety disorders and dementia. We performed a genome-wide association study in 2,235 participants drawn from a population-based study of neuroticism, making this the largest association study for neuroticism to date. Neuroticism was measured by the Eysenck Personality Questionnaire. After Quality Control, we analysed 430,000 autosomal SNPs together with an additional 1.2 million SNPs imputed with high quality from the Hap Map CEU samples. We found a very small effect of population stratification, corrected using one principal component, and some cryptic kinship that required no correction. NKAIN2 showed suggestive evidence of association with neuroticism as a main effect (p<10−6) and GPC6 showed suggestive evidence for interaction with age (p≈10−7). We found support for one previously-reported association (PDE4D), but failed to replicate other recent reports. These results suggest common SNP variation does not strongly influence neuroticism. Our study was powered to detect almost all SNPs explaining at least 2% of heritability, and so our results effectively exclude the existence of loci having a major effect on neuroticism