Typical brain development follows a protracted trajectory throughout childhood and adolescence. Deviations from typical growth trajectories have been implicated in neurodevelopmental and psychiatric ...disorders. Recently, the use of machine learning algorithms to model age as a function of structural or functional brain properties has been used to examine advanced or delayed brain maturation in healthy and clinical populations. Termed ‘brain age’, this approach often relies on complex, nonlinear models that can be difficult to interpret. In this study, we use model explanation methods to examine the cortical features that contribute to brain age modelling on an individual basis.
In a large cohort of n = 768 typically-developing children (aged 3–21 years), we build models of brain development using three different machine learning approaches. We employ SHAP, a model-agnostic technique to identify sample-specific feature importance, to identify regional cortical metrics that explain errors in brain age prediction. We find that, on average, brain age prediction and the cortical features that explain model predictions are consistent across model types and reflect previously reported patterns of regions brain development. However, while several regions are found to contribute to brain age prediction error, we find little spatial correspondence between individual estimates of feature importance, even when matched for age, sex and brain age prediction error. We also find no association between brain age error and cognitive performance in this typically-developing sample.
Overall, this study shows that, while brain age estimates based on cortical development are relatively robust and consistent across model types and preprocessing strategies, significant between-subject variation exists in the features that explain erroneous brain age predictions on an individual level.
Good mental health literacy in young people and their key helpers may lead to better outcomes for those with mental disorders, either by facilitating early help‐seeking by young people themselves, or ...by helping adults to identify early signs of mental disorders and seek help on their behalf.
Few interventions to improve mental health literacy of young people and their helpers have been evaluated, and even fewer have been well evaluated.
There are four categories of interventions to improve mental health literacy: whole‐of‐community campaigns; community campaigns aimed at a youth audience; school‐based interventions teaching help‐seeking skills, mental health literacy, or resilience; and programs training individuals to better intervene in a mental health crisis.
The effectiveness of future interventions could be enhanced by using specific health promotion models to guide their development.
•The fixel-based analysis framework was proposed for fibre-specific statistical analysis of diffusion MRI data.•A “fixel” represents an individual fibre population in a voxel, allowing for increased ...specificity over voxel-wise measures.•A state-of-the-art fixel-based analysis pipeline consists of several bespoke steps, but is conceptually similar to a voxel-based analysis.•Fixel-based analysis has seen increased adoption recently, with 75 published studies to date.•The framework has unique benefits and future opportunities, but specific challenges and limitations exist as well.
Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple “crossing” fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the “Fixel-Based Analysis” (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities.
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Background:
teen Mental Health First Aid (tMHFA) is a classroom-based training programme for students aged 15–18 years to improve supportive behaviours towards peers, increase mental health literacy ...and reduce stigma. This research evaluated tMHFA by comparing it to a matched emergency Physical First Aid (PFA) training programme.
Methods:
A cluster-randomised crossover trial matched four public schools in two pairs and then randomised each to first receive tMHFA or PFA for all Year 10 students. In the subsequent calendar year, the new Year 10 cohort received the opposite intervention, giving eight cohorts. Online surveys were administered at baseline and 1 week post-training, measuring quality of first aid intentions, mental health literacy, problem recognition and stigmatising beliefs, towards fictional adolescents with depression and suicidality (John) and social anxiety (Jeanie).
Results:
A total of 1942 students were randomised (979 received tMHFA, 948 received PFA), 1605 (84%) analysed for the John vignette at baseline and 1116 (69% of baseline) provided post-training data. The primary outcomes, ‘helpful first aid intentions’ towards John/Jeanie, showed significant group-by-time interactions with medium effect sizes favouring tMHFA (ds = 0.50–0.58). Compared to PFA, tMHFA students also reported significantly greater improvements in confidence supporting a peer (ds = 0.22–0.37) and number of adults rated as helpful (ds = 0.45–0.46) and greater reductions in stigmatising beliefs (ds = 0.12–0.40) and ‘harmful first aid intentions’ towards John/Jeanie (ds = 0.15–0.41).
Conclusions:
tMHFA is an effective and feasible programme for increasing supportive first aid intentions and mental health literacy in adolescents in the short term. tMHFA could be widely disseminated to positively impact on help seeking for adolescent mental illness.
Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a ...molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.
Climate change has taken centre stage in European and international politics. Since the second half of the 1980s, the EU has established itself as an international leader on climate change and has ...considerably improved its leadership record. The Union has significantly enhanced both its external representation and its internal climate policies. However, implementation and policy coherence, coordination of EU environmental diplomacy, an evolving international agenda, EU enlargement, and a still precarious EU unity remain major challenges. Shifts in underlying driving forces and advances of EU domestic climate and energy policies nevertheless support the expectation that the EU will remain a progressive force in international climate policy for some time.
Objectives:
The aims of this study were to assess evidence for a novel, universal mental health literacy programme in the school setting (teen Mental Health First Aid) as an intervention to improve ...peer support towards adolescents at risk of suicide and to examine whether participation in a school-based programme dealing with suicide was distressing to participants.
Method:
In a cluster randomised crossover trial, Australian high school students aged 15–17 years (N = 1605, 44.74% female, Mage = 15.87) received either teen Mental Health First Aid or a matched control physical first aid course. Data were collected before, immediately after and 12 months after training through online surveys assessing correct recognition of suicidality and intentions to help a fictional peer (John) who was depicted as experiencing depressive symptoms and suicidal thoughts in a vignette. Students were also asked whether any information in the training or surveys was found distressing and completed a validated measure of psychological distress (the Kessler Psychological Distress Scale).
Results:
Students receiving teen Mental Health First Aid training were much more likely to report an increase from pre- to post-training in recognition of suicidality (OR = 1.97, 95% CI = 1.14, 3.39, p = 0.02) and appropriate first aid intentions towards a peer at risk of suicide than students receiving physical first aid (OR = 35.40, 95% CI = 19.86, 63.14, p < 0.001). Twelve months after training, most effects were still significant. Although a greater proportion of teen Mental Health First Aid participants self-reported feeling briefly distressed after the training, there was no evidence of greater distress at 12 months on the Kessler Psychological Distress Scale.
Conclusion:
teen Mental Health First Aid is effective in increasing recognition of and intentions to assist a suicidal peer. Although the open discussion of mental health first aid for a suicidal peer was distressing for some students, results suggest this was transient and not associated with harm. Future studies are required to ascertain whether these increases are indeed associated with better provision of support and prevention of youth suicide.
Summary
Endothelial cell (EC) activation plays a key role in the pathogenesis of pulmonary microvascular occlusion, which is a hallmark of severe coronavirus disease 2019 (COVID‐19). Consistent with ...EC activation, increased plasma von Willebrand factor antigen (VWF:Ag) levels have been reported in COVID‐19. Importantly however, studies in other microangiopathies have shown that plasma VWF propeptide (VWFpp) is a more sensitive and specific measure of acute EC activation. In the present study, we further investigated the nature of EC activation in severe COVID‐19. Markedly increased plasma VWF:Ag median (interquatile range, IQR) 608·8 (531–830)iu/dl and pro‐coagulant factor VIII (FVIII) levels median (IQR) 261·9 (170–315) iu/dl were seen in patients with severe severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection. Sequential testing showed that these elevated VWF–FVIII complex levels remained high for up to 3 weeks. Similarly, plasma VWFpp levels were also markedly elevated median (IQR) 324·6 (267–524) iu/dl. Interestingly however, the VWFpp/VWF:Ag ratio was reduced, demonstrating that decreased VWF clearance contributes to the elevated plasma VWF:Ag levels in severe COVID‐19. Importantly, plasma VWFpp levels also correlated with clinical severity indices including the Sequential Organ Failure Assessment (SOFA) score, Sepsis‐Induced Coagulopathy (SIC) score and the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F ratio). Collectively, these findings support the hypothesis that sustained fulminant EC activation is occurring in severe COVID‐19, and further suggest that VWFpp may have a role as a biomarker in this setting.
It is well documented that infants born very preterm (VP) are at risk of brain injury and altered brain development in the neonatal period, however there is a lack of long-term, longitudinal studies ...on the effects of VP birth on white matter development over childhood. Most previous studies were based on voxel-averaged, non-fibre-specific diffusion magnetic resonance imaging (MRI) measures, such as fractional anisotropy. In contrast, the novel diffusion MRI analysis framework, fixel-based analysis (FBA), enables whole-brain analysis of microstructural and macrostructural properties of individual fibre populations at a sub-voxel level. We applied FBA to investigate the long-term implications of VP birth and associated perinatal risk factors on fibre development in childhood and adolescence.
Diffusion images were acquired for a cohort of VP (born <30 weeks’ gestation) and full-term (FT, ≥37 weeks’ gestation) children at two timepoints: mean (SD) 7.6 (0.2) years (n = 138 VP and 32 FT children) and 13.3 (0.4) years (n = 130 VP and 45 FT children). 103 VP and 21 FT children had images at both ages for longitudinal analysis. At every fixel (individual fibre population within an image voxel) across the white matter, we compared FBA metrics (fibre density (FD), cross-section (FC) and a combination of these properties (FDC)) between VP and FT groups cross-sectionally at each timepoint, and longitudinally between timepoints. We also examined associations between known perinatal risk factors and FBA metrics in the VP group.
Compared with FT children, VP children had lower FD, FC and FDC throughout the white matter, particularly in the corpus callosum, tapetum, inferior fronto-occipital fasciculus, fornix and cingulum at ages 7 and 13 years, as well as the corticospinal tract and anterior limb of the internal capsule at age 13 years. VP children also had slower FDC development in the corpus callosum and corticospinal tract between ages 7 and 13 years compared with FT children. Within VP children, earlier gestational age at birth, lower birth weight z-score, and neonatal brain abnormalities were associated with lower FD, FC and FDC throughout the white matter at both ages.
VP birth and concomitant perinatal risk factors are associated with fibre tract-specific alterations to axonal development in childhood and adolescence.
•We present a fixel-based analysis in preterm-born children relative to controls.•Preterms have widespread fibre density and cross-section reductions at age 7 and 13.•Longitudinally, preterms have slower development of commissural and motor fibres.•Gestational age, birth weight and brain abnormalities relate to fibre alterations.
Serial regional brain growth from the newborn period to adolescence has not been described. Here, we measured regional brain growth in 216 very preterm (VP) and 45 full-term (FT) children. Brain MRI ...was performed at term-equivalent age, 7 and 13 years in 82 regions. Brain volumes increased between term-equivalent and 7 years, with faster growth in the FT than VP group. Perinatal brain abnormality was associated with less increase in brain volume between term-equivalent and 7 years in the VP group. Between 7 and 13 years, volumes were relatively stable, with some subcortical and cortical regions increasing while others reduced. Notably, VP infants continued to lag, with overall brain size generally less than that of FT peers at 13 years. Parieto-frontal growth, mainly between 7 and 13 years in FT children, was associated with higher intelligence at 13 years. This study improves understanding of typical and atypical regional brain growth.
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