Co-Creative Partnership for Practice: An Application of Dedicated Education Units (DEU). Interprofessional Symposium presentation

This presentation identifies how utilising Dedicated Education Units (DEUs) as a situated learning approach within clinical teaching enhances both student and clinical practice experiences

Primary care transformation in Scotland:qualitative evaluation of the views of patients

BackgroundThe new Scottish GP contract introduced in April 2018 aims to improve quality of care through expansion of the multidisciplinary team (MDT) to enable GPs to spend more time as expert medical generalist with patients with complex needs.AimTo explore patients’ views on the changes in general practice in Scotland since the inception of the new contract.Design and SettingQualitative study with 30 patients (10 living in urban deprived areas, 10 living in urban affluent/mixed urban areas, and 10 living in remote and rural areas).MethodsIn-depth semi-structured interviews with thematic analysis. ResultsPatients were generally unaware of the new GP contract, attributing recent changes in general practice to the COVID-19 pandemic. Ongoing concerns included access to GP consultations (especially face-to-face ones), short consultation length with GPs, and damage to continuity of care and the GP-patient relationship. Most patients spoke positively about consultations with MDT staff but still wanted to see a known GP for health concerns that they considered potentially serious. These issues were especially concerning for patients with multiple complex problems, particularly those from deprived areas. ConclusionFollowing the introduction of the new Scottish GP contract, patients in our sample were accepting of first contact care from the MDT but still wanted continuity of care and longer face-to-face consultations with GPs. These findings suggest that the expert generalist role of the GP is not being adequately supported by the new contract, especially in deprived areas, though further quantitative research is required to confirm this. Key words: Primary care transformation, reform, GP contract, patients’ views, multimorbidity, deprivation<br/

Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease.

C9ORF72 mutations are found in a significant fraction of patients suffering from amyotrophic lateral sclerosis and frontotemporal dementia, yet the function of the C9ORF72 gene product remains poorly understood. We show that mice harboring loss-of-function mutations in the ortholog of C9ORF72 develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant mouse bone marrow into wild-type recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wild-type mouse bone marrow into mutant mice improved their phenotype. We conclude that C9ORF72 serves an important function within the hematopoietic system to restrict inflammation and the development of autoimmunity

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

New label no progress: institutional racism and the persistent segregation of Romani students in the Czech Republic

The over-representation of Romani children in special schools in the Czech Republic is well documented and widely condemned. In 2007 the European Court of Human Rights found the state guilty of discrimination against Romani children on the basis of disproportionate placement of children in remedial special schools. In 2015 high numbers of Romani children are still being misdiagnosed with Special Educational Needs and offered a limited and inappropriate education. This article explores the challenges which continue to hamper their successful inclusion in the Czech education system. Using Critical Race Theory as a lens to examine the Czech case, problems with the current policy trajectory are identified. The article shows that institutional racism persists in the Czech Republic, shaping attitudes and practices at all levels. Policy makers demonstrate little recognition of ingrained educational inequalities and Roma continue to be widely perceived as ‘others’ who must learn to adapt to Czech ways rather than as citizens who are entitled to services on their own terms

The effects of financial vulnerability and mothers’ emotional distress on child social, emotional and behavioural wellbeing: a structural equation model

This article aims to understand the pathways through which financial vulnerability affects children&rsquo;s social, emotional and behavioural (SEB) well-being and whether that impact is directly experienced or, as hypothesised, indirectly through their mothers&rsquo; emotional well-being. It uses data from Growing Up in Scotland &ndash; a longitudinal birth cohort study of 5217 children born in 2004&ndash;2005. The results show that maternal emotional distress is strongly associated with financial vulnerability, more so than with income, and that child SEB well-being is negatively associated with financial vulnerability and maternal emotional distress, with two-thirds of the effect of financial vulnerability being experienced indirectly through maternal emotional distress. While the qualitative evidence shows that financial vulnerability adversely affects older children directly, through the comparisons they make to their reference group, the quantitative finding is that young children are also negatively affected but predominantly via the effect of financial vulnerability on their mothers&rsquo; emotional distress

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

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

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