Residential school placements for children and young people with intellectual disabilities: their use and implications for adult social care

Out of area residential placements are associated with a range of poor outcomes for adults with intellectual disabilities and behaviours that challenge. In recent years there has been an increased drive to reduce such placements at as early a stage as possible. In this context the current review collates research and policy regarding use of residential schools for children and young people with intellectual disabilities and transition from these settings to adult services. The review highlights that relatively little is known about both use of, and transition from, residential schooling for children and young people with intellectual disabilities in the UK. Thirteen articles are identified: 7 examining the child or families’ experiences before placement, 4 examining outcomes during the placement, and 4 examining the process of transitioning from the placement and longer term outcomes. The methodological quality of articles was often limited. A lack of control groups, independent samples, or adequate sample sizes was particularly notable. Results are discussed in relation to factors that lead to a child’s placement in a residential school, children and families’ experiences of the placement, and outcomes following placement, including the transition process. A number of research priorities are highlighted based on gaps in the literature. Examples of alternative forms of support from clinical practice are provided, with recognition that a multi-element model is likely to be needed to provide high quality support to this group of young people

New ways of seeing and being: Evaluating an acceptance and mindfulness group for parents of young people with intellectual disabilities who display challenging behaviour

The current study presents findings from an acceptance and commitment therapy-based intervention for family carers of children who have an intellectual/developmental disability and display high levels of challenging behaviour. The parent well-being workshops consist of two workshops incorporating acceptance and mindfulness-based exercises and discussions. Semi-structured interviews were conducted with five family carers following attendance of the workshops. Participants found the workshops useful and reported that they were better able to cope with stress. They also described how they had incorporated mindfulness into their daily lives and how their practice had had positive effects on their own well-being and on those around them (e.g. their child). Implications of the findings are discussed with emphasis on how the workshops can be included within a positive behaviour support framework. Future directions include a more robust quantitative evaluation, inclusion of follow-up sessions and the application of the workshops with other client groups and in other delivery formats

An exploration into the impact of exposure to community violence and hope on children's perceptions of well-being: a South African perspective

The study aims to explore the relationship between exposure to community violence, hope, and well-being. More specifically, the study aims to ascertain whether hope is a stronger predictor of well-being than exposure to violence. Stratified random sampling was used to select a sample of 566 adolescents aged 14–17 years, from both high violence and low violence areas in Cape Town, South Africa. A questionnaire consisting of Snyder’s Children’s Hope Scale, the Recent Exposure to Violence Scale and the KIDSCREEN-52 was used. Data analysis techniques included descriptive statistics, correlations, and multiple regression. A positive, significant relationship was found between children’s hope and their well-being. Although exposure to community violence was found to be significantly correlated with wellbeing, the relationship was negligible.While exposure to community violence and hope were found to be significant predictors of well-being, hope emerged as a stronger predictor of child well-being than exposure to community violence.Department of HE and Training approved lis

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Rates of breastfeeding and exposure to socio-economic adversity amongst children with intellectual disability

Children with intellectual disability are at increased risk of experiencing poor health relative to their typically developing peers. Previous research indicates that exposure to socio-economic disadvantage contributes towards this disparity but that additional factors (including parenting practices) may be involved in mediating/moderating pathways. This study examined duration of breastfeeding amongst children with and without intellectual disability by a secondary analysis of data from the UK Millennium Cohort Study. Children with intellectual disability were significantly less likely to have been ever breastfed; breastfed exclusively or at all at 3 months or breastfed at all at 6 months relative to children without intellectual disability. None of these differences remained significant when other psycho-social risk factors for reduced breastfeeding were controlled for. The study adds to both the sparse literature on breastfeeding practices amongst families of children with intellectual disability and research demonstrating relationships between socio-economic disadvantage and wellbeing for children with intellectual disability

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies