Background: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10^–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions: Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

Introduction Rare diseases (RDs) are often chronic and progressive life-threatening medical conditions that affect a low percentage of the population compared with other diseases. These conditions can be treated with medications known as orphan drugs (ODs). Unfortunately, there is no universal definition of RDs or ODs. This systematic review (SR) will identify the quantitative and qualitative criteria and the underlying rationale used internationally to define RDs and ODs. Methods and analysis This protocol follows the conventions for the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (2015 guidelines). A SR will be conducted, including a search of the following databases: PubMed, MEDLINE, EMBASE, Scopus, Web of Science, GreyLit and OpenGrey. Eligible publications will be selected based on predetermined inclusion criteria. Extracted data will be analysed using thematic and content analyses of qualitative descriptors, whereas quantitative data will be analysed descriptively and reported in the form of frequencies and percentages. Ethics and dissemination No ethical approval is required since this SR focuses on the secondary analysis of data retrieved from the scientific literature. The outcomes of this SR will be published as part of a PhD thesis, presented at conferences, and published in peer-reviewed journals. PROSPERO registration number CRD42021252701.

This multiple case study was used to explore students’ perceptions of what constitutes verbal feedback and what impacts their receipt and use of feedback. Interpretivist research was undertaken in a rural mixed secondary school in Cornwall, UK involving four year nine students (aged 13–14 years) from two separate classes over eleven weeks. Learning diaries, semi-structured observations and semi-structured group interviews were the methods used to ascertain student perceptions of the delivery of verbal feedback. Thematic, inductive analysis was used to analyse the data. Findings demonstrated that students perceived verbal feedback as a form of focused conversation, different to normal classroom dialogue, identifiable by signals such as personal and task goals. Students sought clarity through verbal feedback, one method of which was dialogue with the teacher, which was desired but not always present. The complexities of the feedback process and the recognition that learners believe variables such as emotion, atmosphere and expectations impact upon it are highlighted. Further research into teacher and student expectations and the role of teacher emotions in the feedback process would be beneficial.

Rare cancers comprise almost a quarter of all cancers in Europe, and patients generally have poorer outcomes than those suffering from more common cancers. This is attributed in part to a general lack of knowledge and awareness of rare cancers. This review aims to examine the communication strategies being used throughout the world to inform on rare cancers and to highlight any opportunities for improvement. A systematic review of literature published in English prior to November 2018 will be conducted, screening articles from the electronic databases MEDLINE, PubMed, EMBASE, Web of Science, PsycINFO, CINAHL Plus and the Cochrane Database of Systematic Reviews. Grey literature databases (GreyLit, OpenGrey) will also be searched in order to screen for any unpublished works. As well as primary literature, reference lists will be examined via forward and reverse citation screening. The review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Titles and abstracts will first be examined for eligibility, with remaining studies undergoing a full-text screening before being included in the final review. Individual studies will be screened for bias, and a meta-analysis performed provided there is enough data. If insufficient homogenous literature exists, a narrative summary of the literature will be produced. Despite the broad topic and width of study type that will be considered, this review hopes to provide a reflective summary of the communication strategies available for people living with and working with rare cancer. It aims to reveal any gaps in the resources available, to contribute to the long-term improvement of diagnosis and management of rare cancers. PROSPERO CRD42018099784

Background: The UK 100,000 Genomes Project was a transformational research project which facilitated whole genome sequencing (WGS) diagnostics for rare diseases. We evaluated experiences of introducing WGS in Northern Ireland, providing recommendations for future projects. Methods: This formative evaluation included (1) an appraisal of the logistics of implementing and delivering WGS, (2) a survey of participant self-reported views and experiences, (3) semi-structured interviews with healthcare staff as key informants who were involved in the delivery of WGS and (4) a workshop discussion about interprofessional collaboration with respect to molecular diagnostics. Results: We engaged with >400 participants, with detailed reflections obtained from 74 participants including patients, caregivers, key National Health Service (NHS) informants, and researchers (patient survey n = 42; semi-structured interviews n = 19; attendees of the discussion workshop n = 13). Overarching themes included the need to improve rare disease awareness, education, and support services, as well as interprofessional collaboration being central to an effective, mainstreamed molecular diagnostic service. Conclusions: Recommendations for streamlining precision medicine for patients with rare diseases include administrative improvements (e.g., streamlining of the consent process), educational improvements (e.g., rare disease training provided from undergraduate to postgraduate education alongside genomics training for non-genetic specialists) and analytical improvements (e.g., multidisciplinary collaboration and improved computational infrastructure).

Rare ophthalmic conditions often cause degenerative vision loss which leads to loss of independence, ability to work and ultimately quality life. Differential methylation is an epigenomic marker that is a feature of several diseases, including eye conditions. This review will aim to elucidate the extent to which differential methylation has been identified in rare ophthalmic conditions. A systematic review will be conducted of articles found in the electronic databases MEDLINE, EMBASE, PubMed and Cochrane Library of Systematic Reviews. Grey literature databases GreyLit and OpenGrey will be searched for relevant unpublished sources. Reference lists of articles which meet eligibility criteria will also be screened for forward and reverse citations. Eligibility criteria will include quantitative articles published, before July 2018, written in English and featuring analysis of differential methylation in rare ophthalmic disorders. Studies will be screened firstly by title, abstract and keywords and then by full text for any remaining sources, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data extraction of key characteristics will be completed using customised forms. Methodological rigour will be assessed using customised forms modelled on the Joanna Briggs Institute critical appraisal forms. This systematic review will enable us to identify if differential methylation can be used to characterise rare ophthalmic disease, which could have crucial implications for improving the accuracy and speed of diagnosis, identifying novel therapeutic targets to reduce or prevent vision loss and overall improving understanding of rare ophthalmic disease. PROSPERO CRD42018094231