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Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.
The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.
There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.
Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.
We present two studies on neural network architectures that learn to represent sentences by composing their words according to automatically induced binary trees, without ever being shown a correct parse tree. We use Tree-Long Short-Term Memories (LSTMs) as our composition function, applied along a tree structure found by a differentiable natural language chart parser. The models simultaneously optimise both the composition function and the parser, thus eliminating the need for externally provided parse trees, which are normally required for Tree-LSTMs. They can therefore be seen as tree-based recurrent neural networks that are unsupervised with respect to the parse trees. Due to being fully differentiable, the models are easily trained with an off-the-shelf gradient descent method and backpropagation.
In the first part of this paper, we introduce a model based on the CKY chart parser, and evaluate its downstream performance on a natural language inference task and a reverse dictionary task. Further, we show how its performance can be improved with an attention mechanism which fully exploits the parse chart, by attending over all possible subspans of the sentence. We find that our approach is competitive against similar models of comparable size and outperforms Tree-LSTMs that use trees produced by a parser.
Finally, we present an alternative architecture based on a shift-reduce parser. We perform an analysis of the trees induced by both our models, to investigate whether they are consistent with each other and across re-runs, and whether they resemble the trees produced by a standard parser.
Material and social environmental stressors affect mental health in
adolescence. Protective factors such as social support from family and
friends may help to buffer the effects of adversity.
The association of violence exposure and emotional disorders was examined
in Cape Town adolescents.
A total of 1034 Grade 8 high school students participated from seven
government co-educational schools in Cape Town, South Africa. Exposure to
violence in the past 12 months and post-traumatic stress disorder (PTSD)
symptoms were measured by the Harvard Trauma Questionnaire, depressive
and anxiety symptoms by the Short Moods and Feelings Questionnaire and
the Self-Rating Anxiety Scale.
Exposure to violence was associated with high scores on depressive (odds
ratio (OR)=6.23, 95% CI 4.2–9.2), anxiety (OR=5.40, 95% CI 2.4–12.4) and
PTSD symptoms (OR=8.93, 95% CI 2.9–27.2) and increased risk of self-harm
(OR=5.72, 95% CI 1.2–25.9) adjusting for gender and social support.
We found that high exposure to violence was associated with high levels
of emotional disorders in adolescents that was not buffered by social
support. There is an urgent need for interventions to reduce exposure to
violence in young people in this setting.
Healthy adults (n 30) participated in a placebo-controlled, randomised, double-blinded, cross-over study consisting of two 28 d treatments (β2-1 fructan or maltodextrin; 3×5 g/d) separated by a 14-d washout. Subjects provided 1 d faecal collections at days 0 and 28 of each treatment. The ability of faecal bacteria to metabolise β2-1 fructan was common; eighty-seven species (thirty genera, and four phyla) were isolated using anaerobic medium containing β2-1 fructan as the sole carbohydrate source. β2-1 fructan altered the faecal community as determined through analysis of terminal restriction fragment length polymorphisms and 16S rRNA genes. Supplementation with β2-1 fructan reduced faecal community richness, and two patterns of community change were observed. In most subjects, β2-1 fructan reduced the content of phylotypes aligning within the Bacteroides, whereas increasing those aligning within bifidobacteria, Faecalibacterium and the family Lachnospiraceae. In the remaining subjects, supplementation increased the abundance of Bacteroidetes and to a lesser extent bifidobacteria, accompanied by decreases within the Faecalibacterium and family Lachnospiraceae. β2-1 Fructan had no impact on the metagenome or glycoside hydrolase profiles in faeces from four subjects. Few relationships were found between the faecal bacterial community and various host parameters; Bacteroidetes content correlated with faecal propionate, subjects whose faecal community contained higher Bacteroidetes produced more caproic acid independent of treatment, and subjects having lower faecal Bacteroidetes exhibited increased concentrations of serum lipopolysaccharide and lipopolysaccharide binding protein independent of treatment. We found no evidence to support a defined health benefit for the use of β2-1 fructans in healthy subjects.
OBJECTIVES/SPECIFIC AIMS: The current treatment for amyotrophic lateral sclerosis (ALS) includes systemic delivery of neurotrophic factors (NTFs). Although this approach may seem theoretically sound, NTF efficacy within the central nervous system (CNS) is largely limited by the blood-brain barrier. Thus, a cell-based approach, which allows for targeted delivery of molecular therapies locally from the CNS, could lead to a paradigm shift in the field. METHODS/STUDY POPULATION: The Windebank and Staff group at Mayo Clinic completed a Phase I dose-escalation safety trial of autologous, adipose-derived mesenchymal stem cells (adMSCs) in an effort to move toward personalized medical treatment of ALS. The adMSCs were injected into the intrathecal space by lumbar puncture in 27 patients and the results showed an excellent safety profile across a range of doses. The team is moving forward with this idea by using gene-editing technology to develop clinical-grade, genetically modified autologous MSCs. The patient-derived adMSCs are modified at defined “safe-harbor” regions of the human genome through transcription activator-like effector nuclease (TALEN) technology. RESULTS/ANTICIPATED RESULTS: Our results show that electroporating adMSCs with plasmid DNA leads to efficient GFP or TALEN transgene expression, but yields low cell survival and a low rate of genetic modification. DISCUSSION/SIGNIFICANCE OF IMPACT: It can be concluded that: (1) TALEN technology may be used to target safe harbor loci for gene integration to produce therapeutic adMSC for ALS. (2) Primary barriers to adMSC modification are inefficient TALEN and donor template uptake, low cutting efficiency, and poor cell survival after electroporation. Future directions include optimizing the protocol to obtain 48 base pairs in the homology arms and increasing transfection efficiency.
To assess the relative validity of the latest version of the Scottish Collaborative Group (SCG) FFQ (version 6.6) in adults living in Scotland.
A cross-sectional validation study. Participants completed the self-administered, 169-item SCG FFQ followed by a 7 d, non-weighed food diary. Energy and energy-adjusted macronutrients and micronutrients were examined for relative validity through Spearman’s correlation, the percentage of classification into thirds of intake, Cohen’s weighted kappa (κw) and Bland–Altman analysis.
General population living in Scotland.
Ninety-six adults aged 18–65 years.
Spearman’s correlation coefficients ranged from 0·21 (retinol) to 0·71 (Mg). A median of 52 % of adults were correctly classified into thirds of intake (range: 42 % (PUFA, MUFA and Fe) to 64 % (percentage energy from carbohydrates)) and 8 % were grossly misclassified into opposite thirds of intake (range: 3 % (carbohydrates, percentage energy from carbohydrates) to 19 % (thiamin)). Values of κw ranged between 0·20 (PUFA, β-carotene) to 0·55 (percentage energy from carbohydrates). In the Bland–Altman analysis, the smallest limits of agreement, when expressed as a percentage of the mean intake from the FFQ and food diary, were seen for the main macronutrients carbohydrates, fat and protein.
As in the previous validation study more than 10 years ago, the FFQ gave higher estimates of energy and most nutrients than the food diary, but after adjustment for energy intake the FFQ could be used in place of non-weighed food diaries for most macronutrients and many micronutrients in large-scale epidemiological studies.
Philosophical pagans in late antiquity charged Christians with believing ‘without evidence’, but were themselves accused of arbitrariness in their initial choice of philosophical school. Stoics and Platonists in particular adopted a form of cosmic religion that Christians criticized on rationalistic as well as sectarian grounds. The other charge levelled against Christians was that they had abandoned ancestral creeds in arrogant disregard of an earlier consensus, and of the world as pagans themselves conceived it. A clearer understanding of the dispute can be gained from a comparison of Heracles and Christ as divinized ‘sons of God’. The hope on both sides was that we might become, or somehow join with, God. Both sought an escape from the image of a pointless, heartless universe – an image that even moderns find difficult to accept and live by. The notion that pagans and Christians had of God, and of the divine life we might hope to share, was almost identical – up to the point, at least, where both philosophical and common pagans conceived God as Pheidias had depicted him (the crowned Master), and Christians rather as the Crucified, ‘risen against the world’.
β2-1 Fructans are purported to improve health by stimulating growth of colonic bifidobacteria, increasing host resistance to pathogens and stimulating the immune system. However, in healthy adults, the benefits of supplementation remain undefined. Adults (thirteen men, seventeen women) participated in a double-blinded, placebo-controlled, randomised, cross-over study consisting of two 28-d treatments separated by a 14-d washout period. Subjects’ regular diets were supplemented with β2-1 fructan or placebo (maltodextrin) at 3×5 g/d. Fasting blood and 1-d faecal collections were obtained at the beginning and at the end of each phase. Blood was analysed for clinical, biochemical and immunological variables. Determinations of well-being and general health, gastrointestinal (GI) symptoms, regularity, faecal SCFA content, residual faecal β2-1 fructans and faecal bifidobacteria content were undertaken. β2-1 Fructan supplementation had no effect on blood lipid or cholesterol concentrations or on circulating lymphocyte and macrophage numbers, but significantly increased serum lipopolysaccharide, faecal SCFA, faecal bifidobacteria and indigestion. With respect to immune function, β2-1 fructan supplementation increased serum IL-4, circulating percentages of CD282+/TLR2+ myeloid dendritic cells and ex vivo responsiveness to a toll-like receptor 2 agonist. β2-1 Fructans also decreased serum IL-10, but did not affect C-reactive protein or serum/faecal Ig concentrations. No differences in host well-being were associated with either treatment, although the self-reported incidence of GI symptoms and headaches increased during the β2-1 fructan phase. Although β2-1 fructan supplementation increased faecal bifidobacteria, this change was not directly related to any of the determined host parameters.
Children and young people placed in out-of-home care are often extremely vulnerable and can require intensive support. Their carers are often faced with significant challenges in effectively responding to their individual needs. This paper is the first in a series of four aimed at supporting carers to make effective responses to challenging behaviours displayed by children and young people in out-of-home care. This paper considers factors that influence an individual child or young person's behaviour as a means of encouraging proactive responses by carers that will address individual need. The series of papers is informed by Edelbrock's (1985) work identifying four clusters of challenging behaviours, with each paper examining one of these clusters. This first paper has a focus on oppositional behaviours. Ensuing papers will examine offensive behaviours, aggressive behaviours and delinquent behaviours respectively.
Children and young people placed in out-of-home care often present with a range of complex and challenging behaviours that place significant stress on carers and other individuals involved in the placement process. The need for practical support, including the facilitation of knowledge sharing opportunities to better support carers and other health care professionals in assisting children and young people in out-of-home care, is of particular importance within the Australian context. This paper is the third in a series of four papers exploring a range of challenging behaviours that may be evidenced in children and young people placed in out-of-home care. The paper focuses on aggressive behaviours in children and adolescents and outlines a working framework to assist carers in responding appropriately to aggressive responses within the out-of-home care context.
Children and young people in out-of-home care experience significant challenges in the adjustment process. All family members are affected by the transition of a child or young person into the family and so carers require a unique set of skills and strategies to respond appropriately. This paper is the second in a series of four papers examining responses to a range of challenging behaviours seen in children and young people placed in out-of-home care contexts. The first paper explored strategies that carers could employ to deal with oppositional behaviours identified in the child or young person. This paper considers offensive behaviours that may be evidenced in children and young people, and practical approaches which carers can utilise to respond proactively to such behaviours.
The transition from childhood to young adulthood is often associated with a range of challenges that can be overwhelming for a young person. For young people in out-of-home care, complex histories that may include traumatic personal experiences can make this transition even more problematic, both for the young person and their carers. This is the final paper in a series of four which has focussed on a range of challenging behaviours in children and young people in out-of-home care. This paper examines delinquency and its associated effects on young people and carers and outlines specific considerations for carers and other health professionals in responding appropriately to delinquent behaviours in young people.