Engaging with immigrant students' voices in the school environment: an analysis of policy documents through school websites.

BACKGROUND: For students to feel happy and supported in school, it is important that their views are taken seriously and integrated into school policies. However, limited information is available how the voices of immigrant students are considered in European school contexts. This study generated evidence from written documents to ascertain how student voice practices are described at school websites. METHODS: Between 2 March and 8 April 2021, we reviewed the policy documents publicly available on school websites. The schools located in areas of high immigration in six European countries: Austria, England, Finland, Germany, Romania, and Switzerland. The READ approach was used to guide the steps in the document analysis in the context of policy studies (1) ready the materials, 2) data extraction, 3) data analysis, 4) distil the findings). A combination of qualitative and quantitative approaches with descriptive statistics (n, %, Mean, SD, range) was used for analysis. RESULTS: A total of 412 documents (305 schools) were extracted. Based on reviewing school websites, reviewers'strongly agreed' in seven documents (2%) that information related to seeking student voices could be easily found. On the contrary, in 247 documents (60%), reviewers strongly indicated that information related to seeking student voices was missing. No clear characteristics could be specified to identify those schools were hearing students' voices is well documented. The most common documents including statements related to student voice were anti-bullying or violence prevention strategies (75/412) and mission statements (72/412). CONCLUSIONS: Our document analysis based on publicly accessible school websites suggest that student voices are less frequently described in school written policy documents. Our findings provide a baseline to further monitor activities, not only at school level but also to any governmental and local authorities whose intention is to serve the public and openly share their values and practices with community members. A deeper understanding is further needed about how listening to student voices is realized in daily school practices.

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.

A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of ß-amyloid-(Aß)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aß deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical ß and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aß-preventing (Aß1-19) and Aß-degradation products (Aß1-20 and Aß1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

SLC19A1 Genetic Variation Leads to Altered Thiamine Diphosphate Transport: Implications for the Risk of Developing Wernicke-Korsakoff's Syndrome.

AIMS: Wernicke-Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells. METHODS: Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls. RESULTS: Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case-control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10-11). CONCLUSION: This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells.

Maternal intentions towards infant sleeping practices in Ireland.

AIM: Mortality from Sudden Infant Death Syndrome (SIDS) has reduced by 50%-85% globally. Despite improvements from 1990 to 2009, the Irish SIDS rate has plateaued. Reasons for this are unclear, but may be related to a reduced parental SIDS awareness. Our study aimed to assess intentions regarding infant sleeping practices in mothers in Ireland. METHODS: A cross-sectional survey of post-partum mothers was performed in the Rotunda Hospital over a four month period. Mothers with a history of SIDS, miscarriage or neonatal admissions were excluded. RESULTS: Of 451 participants, unsafe sleeping positions were intended by 15.4%, reduced by Irish ethnicity [AOR = 0.52, 95% CI = 0.277-0.959, P = .036]. Safe sleep locations were intended by 66%, increased by Irish ethnicity [AOR = 2.6, 95% CI = 1.617-4.191, P < .001], and reduced by young maternal age [AOR = 0.15, 95% CI = 0.03-0.713, P = .02]. Maternal smoking was more likely in mothers with lower educational level [AOR = 3.51, 95% CI = 1.169-10.56, P = .03]. Soft bedding use was intended by 34.8%, increased in younger mothers [AOR = 2.28, 95% CI = 1.04-4.98, P = .04]. Breastfeeding was intended by 72.2%, decreased by Irish ethnicity [AOR = 0.14, 95% CI = 0.067-0.271, P < .001], and low maternal education [AOR = 0.22, 95% CI = 0.117-0.406, P < .001]. CONCLUSION: Educational campaigns on safe sleep for infants in Ireland need to address modifiable SIDS risks factors, focusing on younger, non-Irish mothers, with lower educational attainment.

Teachers' views and experiences of student mental health and well-being programmes: A systematic review.

Background: In schools, teachers are often tasked with implementing mental health and well-being programmes. However, little is known about teachers' views on and experiences with implementing these programmes.Aim: The aim of this systematic review was to explore teachers' views and experiences of mental health and well-being intervention programmes developed to promote and protect student mental health.Methods: A systematic review of the empirical literature was conducted using the following databases: Academic Search Complete, APA PsycArticles, APA PsycInfo, British Education Index, Education Full Text (H.W. Wilson), ERIC, Social Sciences Full Text (H.W. Wilson), and SocINDEX with Full Text.Findings: Seven papers met the inclusion criteria. Teachers reported several challenges to the successful implementation of mental health and well-being programmes, including a lack of time allotted in the curriculum, insufficient training, and inadequate interagency support. There was evidence of conflicting opinions regarding the role of teachers in supporting students.Conclusion: It is recommended that mental health and well-being are viewed as central to schools' ethos and that teachers are adequately prepared to implement programmes.

Genetic association and functional characterization of MCPH1 gene variation in bipolar disorder and schizophrenia.

A rare microcephalin 1 gene (MCPH1) variant rs61749465A>G (p.Asp61Gly) with prior evidence for association with schizophrenia (p = 3.78 × 10-7 ) was tested for association in 2,300 bipolar disorder (BPD) participants, 1,930 SCZ participants and 1,820 normal comparison subjects. We report evidence for association of rs61749465A>G with BPD (p = 0.0009). rs61749465 is located in the N-terminal of the BRCT1 domain of MCPH1. Bioinformatic analysis predicted the Asp61Gly substitution to be damaging to MCPH1 function. A second MCPH1 BRCT1 domain variant (rs199422124C>G; p.Thr27Arg), reported to cause autosomal recessive microcephaly, was not detected in the participants tested here. We sought to characterize the functional effects of these variants on MCPH1 function. Cell count assays indicated that rs199422124 allele G had a greater impact on cell survival compared to the G allele of rs61749465. Gene expression analysis combined with gene network and pathway analysis indicated that rs61749465 allele G may impact protein translation and cell cycle control. The evidence for association between rs61749465A>G and psychosis in both BPD and SCZ warrants further replication. Likewise, the data from the functional analyses point to molecular mechanisms that may underlie the proposed MCPH1 mediated risk of psychosis and pathogenesis in autosomal recessive microcephaly require additional experimental validation.

Exome sequence analysis and follow up genotyping implicates rare ULK1 variants to be involved in susceptibility to schizophrenia.

Schizophrenia (SCZ) is a severe, highly heritable psychiatric disorder. Elucidation of the genetic architecture of the disorder will facilitate greater understanding of the altered underlying neurobiological mechanisms. The aim of this study was to identify likely aetiological variants in subjects affected with SCZ. Exome sequence data from a SCZ cas-control sample from Sweden was analysed for likely aetiological variants using a weighted burden test. Suggestive evidence implicated the UNC-51-like kinase (ULK1) gene, and it was observed that four rare variants that were more common in the Swedish SCZ cases were also more common in UK10K SCZ cases, as compared to obesity cases. These three missense variants and one intronic variant were genotyped in the University College London cohort of 1304 SCZ cases and 1348 ethnically matched controls. All four variants were more common in the SCZ cases than controls and combining them produced a result significant at P = 0.02. The results presented here demonstrate the importance of following up exome sequencing studies using additional datasets. The roles of ULK1 in autophagy and mTOR signalling strengthen the case that these pathways may be important in the pathophysiology of SCZ. The findings reported here await independent replication.

A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder.

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.

Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia.

Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] < 0.001) in genes intolerant of loss-of-function (LoF) variation and in genes whose messenger RNAs bind to fragile X mental retardation protein (FMRP). We further delineate the genetic architecture of schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥ 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies.

Genetic variation in the miR-708 gene and its binding targets in bipolar disorder.

OBJECTIVE: rs12576775 was found to be associated with bipolar disorder (BD) in a genome-wide association study (GWAS). The GWAS signal implicates genes for the microRNAs miR-708 and miR-5579 and the first exon of the Odd Oz/ten-m homolog 4 gene (ODZ4). In the present study, miR-708, its surrounding region, and its targets were analyzed for potential BD-associated functional variants. METHODS: The miR-708 gene and surrounding regions were screened for variation using high-resolution melting (HRM) analysis in 1099 cases of BD, followed by genotyping of rare variants in an enlarged sample of 2078 subjects with BD, 1303 subjects with schizophrenia, and 1355 healthy controls. Whole-genome sequencing data from 99 subjects with BD were analyzed for variation in potential miR-708 binding sites. The minor allele frequencies (MAFs) of these variants were compared with those reported in reference individuals. RESULTS: Three variants detected by HRM were selected to be genotyped. rs754333774 was detected in three cases of BD, two cases of schizophrenia, and no controls. This variant is located 260 base pairs upstream from miR-708 and may play a role in controlling the expression of the miR. Four variants were identified in miR-708 targets binding sites. The MAFs of each of these variants were similar in BD and reference samples. CONCLUSIONS: We report a single recurrent variant located near the miR-708 gene that may have a role in BD and schizophrenia susceptibility. These findings await replication in independent cohorts, as do functional analyses of the potential consequences of this variant.

Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data.

OBJECTIVES: Genetic markers in the genes encoding ankyrin 3 (ANK3) and the α-calcium channel subunit (CACNA1C) are associated with bipolar disorder (BP). The associated variants in the CACNA1C gene are mainly within intron 3 of the gene. ANK3 BP-associated variants are in two distinct clusters at the ends of the gene, indicating disease allele heterogeneity. METHODS: In order to screen both coding and non-coding regions to identify potential aetiological variants, we used whole-genome sequencing in 99 BP cases. Variants with markedly different allele frequencies in the BP samples and the 1,000 genomes project European data were genotyped in 1,510 BP cases and 1,095 controls. RESULTS: We found that the CACNA1C intron 3 variant, rs79398153, potentially affecting an ENCyclopedia of DNA Elements (ENCODE)-defined region, showed an association with BP (p = 0.015). We also found the ANK3 BP-associated variant rs139972937, responsible for an asparagine to serine change (p = 0.042). However, a previous study had not found support for an association between rs139972937 and BP. The variants at ANK3 and CACNA1C previously known to be associated with BP were not in linkage disequilibrium with either of the two variants that we identified and these are therefore independent of the previous haplotypes implicated by genome-wide association. CONCLUSIONS: Sequencing in additional BP samples is needed to find the molecular pathology that explains the previous association findings. If changes similar to those we have found can be shown to have an effect on the expression and function of ANK3 and CACNA1C, they might help to explain the so-called 'missing heritability' of BP.

High emotional arousal and failures in reality monitoring: pathways to auditory hallucinations in non-psychotic children?

Recent research has confirmed the presence of auditory hallucinations in non-psychotic children, with this research also suggesting that such hallucinations may be more common than previously thought. While auditory hallucinations in children have frequently been associated with high levels of emotional stress, there is still a poor understanding of how this stress may precipitate hallucinations, and why some children experience hallucinations while others seem not to. The current study assessed the association between high levels of trauma symptomatology, anxiety and depression, and the presence of hallucinations against matched controls. Results indicated that hallucinating children had significantly higher mean anxiety, depression and, in particular, re-experiencing scores than did the children in the control group. These results were examined within the framework of reality monitoring, that is, the ability to distinguish between externally or internally generated sources of information. The notion of high levels of emotional distress decreasing the efficiency of reality monitoring and leading to the possibility of confusion between internally and externally generated stimuli was discussed, with the conclusion advanced that the misattribution of an externally generated source--either held as a memory or as a traumatic re-experiencing--as an internally generated one, underlies hallucinatory experiences.

A cryptic clue to neurodegeneration?

Antisense oligonucleotides rescue cryptic RNA splicing and neuron regeneration.

"We're not educated on that enough, and we really should be": adolescents' views of mental health service education.

PURPOSE: Despite the susceptibility to the experience of mental distress during adolescence, this population often demonstrate poor help-seeking behaviours. Efforts have been made by schools to address adolescents' knowledge around mental health; less focus has been given to addressing their knowledge of mental health services and avenues for help-seeking. This study aimed to explore adolescents' views of mental health services education. METHODS: An interpretive descriptive design was adopted. Thirty adolescents from Ireland participated in individual interviews. Data were analysed using content analysis. TWO THEMES WERE IDENTIFIED: Recognizing Gaps in Knowledge about Mental Health Service Education, and Enhancing Mental Health Service Education for Young People. Participants reported gaps in their knowledge about mental health services and were uncertain how to access help. Current strategies (e.g., print media) were considered tokenistic and ineffective; instead, multimedia (film/TV) approaches were recommended. RESULTS: Two themes were identified: Recognizing Gaps in Knowledge about Mental HealthService Education, and Enhancing Mental Health Service Education for YoungPeople. Participants reported gaps in their knowledge about mental healthservices and were uncertain how to access help. Current strategies (e.g., print media) were considered tokenistic and ineffective; instead, multimedia (film/TV) approaches were recommended. CONCLUSIONS: Current mental health education programmes need to expand their focus beyond social/emotional well-being, providing adolescents with the knowledge they need to access appropriate supports. Considering traditional print media was viewed as ineffective, while film/TV had an influence on perceptions of mental health services, a multimedia approach to education may be an effective way of engaging this population.

Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels.

BACKGROUND: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. METHODS: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. FINDINGS: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. INTERPRETATION: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. FUNDING: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".

Participation in perspective: reflections from research projects.

AIM: This paper seeks to add to the debate regarding children as researchers by exploring the reality of their participation in research. BACKGROUND: As the role children and young people play in knowledge building is recognised, their position as social agents is evolving. This has led to a shift in the ways in which children and young people participate in research, and in particular in their roles as researchers alongside adults. DATA SOURCES: Two participatory research projects involving children and young people. REVIEW METHODS: The paper critiques existing models of children's participation and is followed by an account of observations made during the research projects. DISCUSSION: Existing models offered a variety of criteria against which to measure participation. However, none of the models allowed for the multidimensional nature of participation that emerged from the data to be fully described. CONCLUSION: A dual-axis model of participation is more useful than the other models described in the text for reflecting on participatory processes. IMPLICATIONS FOR PRACTICE/RESEARCH: The model can be valuable in guide planning and implementing participatory research with children and also as a tool for evaluating the process.

Emergency department utilisation by homeless children in Dublin, Ireland: a retrospective review.

INTRODUCTION: Despite increasing prevalence, European family homelessness remains under-researched. METHODS: A retrospective review was performed of homeless children attending a paediatric emergency department in Dublin, Ireland, from 1 January 2017 to 31 December 2020. Comparison was made with a random cohort of 1500 non-homeless paediatric attendances in 2019. Homelessness was defined using the European Typology of Homelessness and Housing Exclusion, including those with addresses of no fixed abode, government homeless accommodation and certain residential settings. The objectives were to compare presentations between homeless and non-homeless children. We were interested in determining differences regarding demographics, healthcare utilisation, clinical presentation and outcomes. RESULTS: Of 197 437 attendances 3138 (1.59%) were homeless. Compared with the non homeless, homeless children were less likely to be ethnically Irish (37.4% vs 74.6%, p<0.001) or have been born in Ireland (82.3% vs 96.2%, p<0.001). Irish Travellers (3% vs 0.8%), Roma (22.5% vs 2.4%) and black (21.1% vs 4.2%) ethnicities were over-represented (p<0.001) in the homeless cohort.Homeless children were younger (age <12 months: 26% vs 16%; p<0.001), less likely to be fully vaccinated (73.6% vs 81.9%, p<0.001) and have registered general practitioners (89.7% vs 95.8%, p<0.001). They were more likely to represent within 2 weeks (15.9% vs 10.5%, p<0.001), and use ambulance transportation (13.2% vs 6.7%, p<0.001). Homeless children had lower acuity presentations (triage category 4-5: 47.2% vs 40.7%, p<0.001) and fewer admissions (5.9% vs 8.4%, p<0.001) than non-homeless children. DISCUSSION: Infants, Irish Travellers, Roma and black ethnicities were over-represented in homeless presentations. Homeless children had increased reliance on emergency services for primary healthcare needs.

Physical education student teachers' wellbeing during Covid-19: Resilience resources and challenges from school placement.

The coronavirus 2019 (Covid-19) pandemic has given rise to significant global challenges across education, and specifically in the physical education teacher education (PETE) community. Students attending teacher education programmes during the Covid-19 pandemic have experienced an abrupt and unprecedented pedagogical transition from a face-to-face capacity to remote teaching, learning, and assessment environments. Crucially, student teachers' school placement experiences faced increased challenges and practical implications from additional environmental and social changes. In the context of continued global and national challenges for initial teacher education (ITE) programmes, the present qualitative study, using a representative sample of 24 student physical education (PE) teachers from a PETE programme, investigates the perceived implications of the Covid-19 pandemic on student teachers' practice and wellbeing during their final 2020/2021 academic year. Results indicate that student teachers maintain that exercise, connections with the university and school placement communities, alongside personal and professional organisation skills serve as resilience resources protecting their wellbeing. Conversely, student teachers express that school placement isolation, restricted PE delivery, increased workload, low teacher efficacy, and the responsibility to implement Covid-19 behaviour regulations presented as challenges that negatively affect their wellbeing. The paper concludes with practices that may further support PETE and ITE programmes and their student teachers to maintain a stable level of wellbeing throughout their careers.