Meanings in motion and faces: Developmental associations between the processing of intention from geometrical animations and gaze detection accuracy

Aspects of face processing, on the one hand, and theory of mind (ToM) tasks, on the other hand, show specific impairment in autism. We aimed to discover whether a correlation between tasks tapping these abilities was evident in typically developing children at two developmental stages. One hundred fifty-four normal children (6-8 years and 16-18 years) and 13 high-IQ autistic children (11-17 years) were tested on a range of face-processing and IQ tasks, and a ToM test based oil the attribution of intentional movement to abstract shapes in a cartoon. By midchildhood, the ability accurately and spontaneously to infer the locus of attention of a face with direct or averted gaze was specifically associated with the ability to describe geometrical animations using mental state terms. Other face-processing and animation descriptions failed to show the association. Autistic adolescents were impaired at both gaze processing and ToM descriptions. using these tests. Mentalizing and gaze perception accuracy are associated in typically developing children and adolescents. The findings are congruent with the possibility that common neural Circuitry underlies, at least in part, processing implicated in these tasks. They are also congruent with the possibility that autism may lie at one end of a developmental continuum with respect to these skills, and to the factor(s) underpinning them

Validating the Developmental and Well-Being Assessment (DAWBA) in a clinical population with high-functioning autism [version 1; peer review: awaiting peer review]

Background: With increasing numbers of referrals to health services for assessment of Autism Spectrum Disorder (ASD), the Developmental and Well-Being Assessment (DAWBA) has been suggested as a useful screening instrument to assist in prioritising patients for review. It is an online interview for parents that has been previously validated for ASD in a non-clinical community sample of twins. Our study aimed to evaluate its predictive validity in a complex clinically-referred sample of children with suspected high-functioning autism. / Methods: The sample comprised 136 children (females = 53; males = 83) who were referred for ASD assessment at the Social Communication Disorder Clinic (SCDC) at Great Ormond Street Hospital. Parents completed the DAWBA online prior to undergoing a multi-disciplinary team (MDT) assessment. This included completing the Developmental, Dimensional and Diagnostic Interview (3di) and the Autism Diagnostic Observation Schedule (ADOS). Two clinicians independently rated the DAWBA using DSM-5 diagnostic criteria and compared results to the MDT outcome, which was considered gold standard. / Results: Compared with an MDT assessment, the DAWBA interview demonstrated good sensitivity (0.91) but poor specificity (0.12). Overall, 64% of cases were accurately assigned as case/non-case. Estimates of positive (0.66) and negative (0.43) predictive validity were influenced by the relatively high prevalence of ASD in the study sample (65%). / Conclusion: The DAWBA online interview has excellent sensitivity in a clinical population of complex neurodevelopmental disorders, containing a high prevalence of ASD, but specificity was poor. As the SCDC offers tertiary opinions on disputed cases of suspected ASD, the population cohort limits the generalisability of these results. Further evaluation is required in community child mental health or paediatric services

The negative impact of global health worker migration, and how it can be addressed

International migration of healthcare workers is well established and has become a means of maintaining service quality in many high income countries. In recent years, there has been a dramatic increase in recruitment of health personnel who have been trained abroad, including from the poorest countries in the world. In this article, using General Medical Council (GMC) data, we chart the growth in numbers of international staff working in the United Kingdom, where since 2018, over half of all new GMC registrations have been of doctors trained abroad. There is evidence that this migration of health staff results in poorer health service provision in low and middle income countries, as well as substantial economic impacts in these countries that have invested in training their health workforce. Recruiting governments have argued that remittances compensate for the loss of personnel, and that training opportunities can enable skills transfer to countries with weaker health systems. However, we found that the costs to the source countries dwarfed remittances, and that only a tiny fraction of people who move to take up posts in wealthier countries ever return to their countries of origin to work. We conclude that in addition to the investment in health systems (and workforce development) in low and middle income countries as part of Official Development Assistance for Health, there is an urgent need to increase training of nurses and doctors so that damaging migration is no longer relied upon to fill gaps in healthcare personnel

White matter microstructure correlates with autism trait severity in a combined clinical–control sample of high-functioning adults

AbstractDiffusion tensor imaging (DTI) studies have demonstrated white matter (WM) abnormalities in tracts involved in emotion processing in autism spectrum disorder (ASD), but little is known regarding the nature and distribution of WM anomalies in relation to ASD trait severity in adults. Increasing evidence suggests that ASD occurs at the extreme of a distribution of social abilities. We aimed to examine WM microstructure as a potential marker for ASD symptom severity in a combined clinical–neurotypical population. SIENAX was used to estimate whole brain volume. Tract-based spatial statistics (TBSS) was used to provide a voxel-wise comparison of WM microstructure in 50 high-functioning young adults: 25 ASD and 25 neurotypical. The severity of ASD traits was measured by autism quotient (AQ); we examined regressions between DTI markers of WM microstructure and ASD trait severity. Cognitive abilities, measured by intelligence quotient, were well-matched between the groups and were controlled in all analyses. There were no significant group differences in whole brain volume. TBSS showed widespread regions of significantly reduced fractional anisotropy (FA) and increased mean diffusivity (MD) and radial diffusivity (RD) in ASD compared with controls. Linear regression analyses in the combined sample showed that average whole WM skeleton FA was negatively influenced by AQ (p=0.004), whilst MD and RD were positively related to AQ (p=0.002; p=0.001). Regression slopes were similar within both groups and strongest for AQ social, communication and attention switching scores. In conclusion, similar regression characteristics were found between WM microstructure and ASD trait severity in a combined sample of ASD and neurotypical adults. WM anomalies were relatively more severe in the clinically diagnosed sample. Both findings suggest that there is a dimensional relationship between WM microstructure and severity of ASD traits from neurotypical subjects through to clinical ASD, with reduced coherence of WM associated with greater ASD symptoms. General cognitive abilities were independent of the relationship between WM indices and ASD traits

The pediatric glucocorticoid toxicity index

Objectives: To develop a Pediatric glucocorticoid toxicity index (pGTI), a standardized, weighted clinical outcome assessment that measures change in glucocorticoid (GC) toxicity over time. Methods: Fourteen physician experts from 7 subspecialties participated. The physician experts represented multiple subspecialties in which GCs play a major role in the treatment of inflammatory disease: nephrology, rheumatology, oncology, endocrinology, genetics, psychiatry, and maternal-fetal medicine. Nine investigators were from Canada, Europe, or New Zealand, and 5 were from the United States. Group consensus methods and multi-criteria decision analysis were used. The pGTI is an aggregate assessment of GC toxicities that are common, important, and dynamic. These toxicities are organized into health domains graded as minor, moderate, or major and are weighted according to severity. The relative weights were derived by group consensus and multi-criteria decision analysis using the 1000MindsTM software platform. Two quantitative scores comprise the overall toxicity profile derived from pGTI data: (1) the Cumulative Worsening Score; and (2) the Aggregate Improvement Score. The pGTI also includes a qualitative, unweighted record of GC side-effects known as the Damage Checklist, which documents less common toxicities that, although potentially severe, are unlikely to change with varying GC dosing. Results: One hundred and seven (107) toxicity items were included in the pGTI and thirty-two (32) in the Damage Checklist. To assess the degree to which the pGTI corresponds to expert clinical judgement, the investigators ranked 15 cases by clinical judgement from highest to lowest GC toxicity. Expert rankings were then compared to case ranking by the pGTI, yielding excellent agreement (weighted kappa 0.86). The pGTI was migrated to a digital environment following its development and initial validation. The digital platform is designed to ensure ease-of-use in the clinic, rigor in application, and accuracy of scoring. Clinic staff enter vital signs, laboratory results, and medication changes relevant to pGTI scoring. Clinicians record findings for GC myopathy, skin toxicity, mood dysfunction, and infection. The pGTI algorithms then apply the weights to these raw data and calculate scores. Embedded logic accounts for the impact of age- and sex-related reference ranges on several health domains: blood pressure, lipid metabolism, and bone mineral density. Other algorithms account for anticipated changes in the height Z-scores used in the growth domain, thereby addressing a concern unique to GC toxicity in children. The Damage Checklist ensures comprehensive measurement of GC toxicity but does not contribute to pGTI scoring, because the scored domains emphasize manifestations of GC toxicity that are likely to change over the course of a trial. Conclusions: We describe the development and initial evaluation of a weighted, composite toxicity index for the assessment of morbidity related to GC use in children and adolescents. Developing the pGTI digital platform was essential for performing the nuanced calculations necessary to ensure rigor, accuracy, and ease-of-use in both clinic and research settings

Eine kurze Geschichte der Metaphysik

A very short history of metaphysics

Widespread sex differences in gene expression and splicing in the adult human brain

There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures

Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals

BACKGROUND: Autism is a heterogeneous collection of disorders with a complex molecular underpinning. Evidence from postmortem brain studies have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from individuals with autism with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism. METHODS: iPSCs were generated from 9 unrelated individuals with autism without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing control individuals. iPSCs were differentiated toward either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterize iPSCs at different stages of differentiation. RESULTS: A subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to postmortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated toward a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs. CONCLUSIONS: Taken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages