Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells

Peer reviewedPublisher PD

Childhood behaviour problems show the greatest gap between DNA-based and twin heritability

For most complex traits, DNA-based heritability (‘SNP heritability’) is roughly half that of twin-based heritability. A previous report from the Twins Early Development Study suggested that this heritability gap is much greater for childhood behaviour problems than for other domains. If true, this finding is important because SNP heritability, not twin heritability, is the ceiling for genome-wide association studies. With twice the sample size as the previous report, we estimated SNP heritabilities (N up to 4653 unrelated individuals) and compared them with twin heritabilities from the same sample (N up to 4724 twin pairs) for diverse domains of childhood behaviour problems as rated by parents, teachers, and children themselves at ages 12 and 16. For 37 behaviour problem measures, the average twin heritability was 0.52, whereas the average SNP heritability was just 0.06. In contrast, results for cognitive and anthropometric traits were more typical (average twin and SNP heritabilities were 0.58 and 0.28, respectively). Future research should continue to investigate the reasons why SNP heritabilities for childhood behaviour problems are so low compared with twin estimates, and find ways to maximise SNP heritability for genome-wide association studies

SPEM dysfunction and general schizotypy as measured by the SSQ: a controlled study

Abstract Background SPEM dysfunction is a well-known phenomenon in schizophrenia. The principal aim of the present study was to examine whether SPEM dysfunction is already observable in subjects scoring high on a specific measure of schizotypy (SSQ General Schizotypy) that was selected because of its intimate relationship with schizophrenic prodromal unfolding. Methods Applying ANOVAs, we determined the relationship of subjects' scores on SSQ General Schizotypy and eye movements elicited by targets of different speed. We also examined whether there exists an association between our schizotypy measure and pupil size. Results We found more SPEM dysfunction in subjects scoring high on SSQ General Schizotypy than in subjects scoring average on that factor, irrespective of the speed of the target. No relationship was found between baseline pupil size and General Schizotypy. Conclusion The present study provides additional evidence that SPEM dysfunction is associated with schizotypic features that precede the onset of schizophrenia and is already observable in general population subjects that show these features

A Three-Stage Genome-Wide Association Study of General Cognitive Ability: Hunting the Small Effects

Childhood general cognitive ability (g) is important for a wide range of outcomes in later life, from school achievement to occupational success and life expectancy. Large-scale association studies will be essential in the quest to identify variants that make up the substantial genetic component implicated by quantitative genetic studies. We conducted a three-stage genome-wide association study for general cognitive ability using over 350,000 single nucleotide polymorphisms (SNPs) in the quantitative extremes of a population sample of 7,900 7-year-old children from the UK Twins Early Development Study. Using two DNA pooling stages to enrich true positives, each of around 1,000 children selected from the extremes of the distribution, and a third individual genotyping stage of over 3,000 children to test for quantitative associations across the normal range, we aimed to home in on genes of small effect. Genome-wide results suggested that our approach was successful in enriching true associations and 28 SNPs were taken forward to individual genotyping in an unselected population sample. However, although we found an enrichment of low P values and identified nine SNPs nominally associated with g (P < 0.05) that show interesting characteristics for follow-up, further replication will be necessary to meet rigorous standards of association. These replications may take advantage of SNP sets to overcome limitations of statistical power. Despite our large sample size and three-stage design, the genes associated with childhood g remain tantalizingly beyond our current reach, providing further evidence for the small effect sizes of individual loci. Larger samples, denser arrays and multiple replications will be necessary in the hunt for the genetic variants that influence human cognitive ability

Sequential morphological characteristics of murine fetal liver hematopoietic microenvironment in Swiss Webster mice

Embryonic hematopoiesis occurs via dynamic development with cells migrating into various organs. Fetal liver is the main hematopoietic organ responsible for hematopoietic cell expansion during embryologic development. We describe the morphological sequential characteristics of murine fetal liver niches that favor the settlement and migration of hematopoietic cells from 12 days post-coitum (dpc) to 0 day post-partum. Liver sections were stained with hematoxylin and eosin, Lennert’s Giemsa, Sirius Red pH 10.2, Gomori’s Reticulin, and Periodic Acid Schiff/Alcian Blue pH 1.0 and pH 2.5 and were analyzed by bright-field microscopy. Indirect imunohistochemistry for fibronectin, matrix metalloproteinase-1 (MMP-1), and MMP-9 and histochemistry for naphthol AS-D chloroacetate esterase (NCAE) were analyzed by confocal microscopy. The results showed that fibronectin was related to the promotion of hepatocyte and trabecular differentiation; reticular fibers did not appear to participate in fetal hematopoiesis but contributed to the physical support of the liver after 18 dpc. During the immature phase, hepatocytes acted as the fundamental stroma for the erythroid lineage. The appearance of myeloid cells in the liver was related to perivascular and subcapsular collagen, and NCAE preceded MMP-1 expression in neutrophils, an occurrence that appeared to contribute to their liver evasion. Thus, the murine fetal liver during ontogenesis shows two different phases: one immature and mainly endodermic (<14 dpc) and the other more developed (endodermic-mesenchymal; >15 dpc) with the maturation of hepatocytes, a better definition of trabecular pattern, and an increase in the connective tissue in the capsule, portal spaces, and liver parenchyma. The decrease of hepatic hematopoiesis (migration) coincides with hepatic maturation

Exploring Predictors of Outcome in the Psychosis Prodrome: Implications for Early Identification and Intervention

Functional disability is a key component of many psychiatric illnesses, particularly schizophrenia. Impairments in social and role functioning are linked to cognitive deficits, a core feature of psychosis. Retrospective analyses demonstrate that substantial functional decline precedes the onset of psychosis. Recent investigations reveal that individuals at clinical-high-risk (CHR) for psychosis show impairments in social relationships, work/school functioning and daily living skills. CHR youth also demonstrate a pattern of impairment across a range of cognitive domains, including social cognition, which is qualitatively similar to that of individuals with schizophrenia. While many studies have sought to elucidate predictors of clinical deterioration, specifically the development of schizophrenia, in such CHR samples, few have investigated factors relevant to psychosocial outcome. This review integrates recent findings regarding cognitive and social-cognitive predictors of outcome in CHR individuals, and proposes potential directions for future research that will contribute to targeted interventions and improved outcome for at-risk youth

Understanding atmospheric organic aerosols via factor analysis of aerosol mass spectrometry: a review

Organic species are an important but poorly characterized constituent of airborne particulate matter. A quantitative understanding of the organic fraction of particles (organic aerosol, OA) is necessary to reduce some of the largest uncertainties that confound the assessment of the radiative forcing of climate and air quality management policies. In recent years, aerosol mass spectrometry has been increasingly relied upon for highly time-resolved characterization of OA chemistry and for elucidation of aerosol sources and lifecycle processes. Aerodyne aerosol mass spectrometers (AMS) are particularly widely used, because of their ability to quantitatively characterize the size-resolved composition of submicron particles (PM1). AMS report the bulk composition and temporal variations of OA in the form of ensemble mass spectra (MS) acquired over short time intervals. Because each MS represents the linear superposition of the spectra of individual components weighed by their concentrations, multivariate factor analysis of the MS matrix has proved effective at retrieving OA factors that offer a quantitative and simplified description of the thousands of individual organic species. The sum of the factors accounts for nearly 100% of the OA mass and each individual factor typically corresponds to a large group of OA constituents with similar chemical composition and temporal behavior that are characteristic of different sources and/or atmospheric processes. The application of this technique in aerosol mass spectrometry has grown rapidly in the last six years. Here we review multivariate factor analysis techniques applied to AMS and other aerosol mass spectrometers, and summarize key findings from field observations. Results that provide valuable information about aerosol sources and, in particular, secondary OA evolution on regional and global scales are highlighted. Advanced methods, for example a-priori constraints on factor mass spectra and the application of factor analysis to combined aerosol and gas phase data are discussed. Integrated analysis of worldwide OA factors is used to present a holistic regional and global description of OA. Finally, different ways in which OA factors can constrain global and regional models are discussed

Self-help interventions for depressive disorders and depressive symptoms: a systematic review

<p>Abstract</p> <p>Background</p> <p>Research suggests that depressive disorders exist on a continuum, with subthreshold symptoms causing considerable population burden and increasing individual risk of developing major depressive disorder. An alternative strategy to professional treatment of subthreshold depression is population promotion of effective self-help interventions that can be easily applied by an individual without professional guidance. The evidence for self-help interventions for depressive symptoms is reviewed in the present work, with the aim of identifying promising interventions that could inform future health promotion campaigns or stimulate further research.</p> <p>Methods</p> <p>A literature search for randomised controlled trials investigating self-help interventions for depressive disorders or depressive symptoms was performed using PubMed, PsycINFO and the Cochrane Database of Systematic Reviews. Reference lists and citations of included studies were also checked. Studies were grouped into those involving participants with depressive disorders or a high level of depressive symptoms, or non-clinically depressed participants not selected for depression. A number of exclusion criteria were applied, including trials with small sample sizes and where the intervention was adjunctive to antidepressants or psychotherapy.</p> <p>Results</p> <p>The majority of interventions searched had no relevant evidence to review. Of the 38 interventions reviewed, the ones with the best evidence of efficacy in depressive disorders were S-adenosylmethionine, St John's wort, bibliotherapy, computerised interventions, distraction, relaxation training, exercise, pleasant activities, sleep deprivation, and light therapy. A number of other interventions showed promise but had received less research attention. Research in non-clinical samples indicated immediate beneficial effects on depressed mood for distraction, exercise, humour, music, negative air ionisation, and singing; while potential for helpful longer-term effects was found for autogenic training, light therapy, omega 3 fatty acids, pets, and prayer. Many of the trials were poor quality and may not generalise to self-help without professional guidance.</p> <p>Conclusion</p> <p>A number of self-help interventions have promising evidence for reducing subthreshold depressive symptoms. Other forms of evidence such as expert consensus may be more appropriate for interventions that are not feasible to evaluate in randomised controlled trials. There needs to be evaluation of whether promotion to the public of effective self-help strategies for subthreshold depressive symptoms could delay or prevent onset of depressive illness, reduce functional impairment, and prevent progression to other undesirable outcomes such as harmful use of substances.</p

Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study.

BACKGROUND: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions. METHODS: We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London). FINDINGS: 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal-external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [-0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model. INTERPRETATION: The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19. FUNDING: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London