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Early-onset Alzheimer’s disease (EOAD) can be familial (FAD) or sporadic (sEOAD); both have a disease onset ≤ 65 years of age. 451 sEOAD samples were screened for known causative mutations in exon 16 and 17 of the Amyloid Precursor Protein gene (APP). Four samples were shown to be heterozygous for one of three known causative mutations: p.A713T, p.V717I and p.V717G, this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a non-significantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6 bp deletion on splicing, COS-7 and BE (2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harbouring the deletion found no evidence of transcripts with exon 17 removed.

Late onset Alzheimer’s disease (LOAD), the most common cause of late onset dementia, has a strong genetic component. To date, 21 disease-risk loci have been identified through genome wide association studies (GWAS). However, the causative functional variant(s) within these loci are yet to be discovered. This study aimed to identify potential functional splicing mutations in the nine original GWAS-risk genes: CLU, PICALM, CR1, ABCA7, BIN1, the MS4A locus, CD2AP, EPHA1 and CD33. Target enriched next generation sequencing (NGS) was used to resequence the entire genetic region for each of these GWAS-risk loci in 96 LOAD patients and in silico databases were used to annotate the variants for functionality. Predicted splicing variants were further functionally characterised using splicing prediction software and minigene splicing assays. Following in silico annotation, 21 variants were predicted to influence splicing and, upon further annotation, four of these were examined utilising the in vitro minigene assay. Two variants, rs881768 A>G in ABCA7 and a novel variant 11: 60179827 T>G in MS4A6A were shown, in these cell assays, to affect the splicing of these genes. The method employed in the paper successfully identified potential splicing variants in GWAS-risk genes. Further investigation will be needed to understand the full effect of these variants on LOAD risk. However, these results suggest a possible pipeline in order to identify putative functional variants as a result of NGS in disease-associated loci although improvements are needed within the current prediction programme in order to reduce the number of false positives.

We have screened sporadic early-onset Alzheimer’s disease (sEOAD, n=408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found two sEOAD individuals harbouring a known causative variant in PARK2 known to cause early-onset Parkinson’s disease (EOPD); p.T240M (n=1) and p.Q34fs delAG (n=1). Additionally, we identified three sEOAD individuals harbouring a predicted pathogenic variant in MAPT (p.A469T) which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer’s disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyse the single independent and joint effect of rare and low frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low frequency coding variant (p.G215S, rs72973581, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR=0.57, 95% CI 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provide new insights that should address functional studies.

Background Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. The levonorgestrel intrauterine device (Mirena Coil, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA) may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown in some human studies to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. Objectives To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. Search methods We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Google Scholar,OpenGrey, Latin American Caribbean Health Sciences Literature (LILACS), and two trials registers from inception to 10 January 2017. We searched the bibliographies of all included studies and reviews on this topic. We also handsearched the conference abstracts of the European Society of Human Reproduction and Embryology (ESHRE) 2015 and the American Society for Reproductive Medicine (ASRM) 2015. Selection criteria We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combinatio

To determine the efficacy and safety of metformin in treating women with endometrial hyperplasia

Objective: To evaluate the current provision and outcome of community-based education (CBE) in UK medical schools. Design and data sources: An online survey of UK medical school websites and course prospectuses and a systematic review of articles from PubMed and Web of Science were conducted. Articles in the systematic review were assessed using Rossi, Lipsey and Freeman’s approach to programme evaluation. Study selection: Publications from November 1998 to 2013 containing information related to community teaching in undergraduate medical courses were included. Results: Out of the 32 undergraduate UK medical schools, one was excluded due to the lack of course specifications available online. Analysis of the remaining 31 medical schools showed that a variety of CBE models are utilised in medical schools across the UK. Twenty-eight medical schools (90.3%) provide CBE in some form by the end of the first year of undergraduate training, and 29 medical schools (93.5%) by the end of the second year. From the 1378 references identified, 29 papers met the inclusion criteria for assessment. It was found that CBE mostly provided advantages to students as well as other participants, including GP tutors and patients. However, there were a few concerns regarding the lack of GP tutors’ knowledge in specialty areas, the negative impact that CBE may have on the delivery of health service in education settings and the cost of CBE. Conclusions: Despite the wide variations in implementation, community teaching was found to be mostly beneficial. To ensure the relevance of CBE for ‘Tomorrow’s Doctors’, a national framework should be established, and solutions sought to reduce the impact of the challenges within CBE. Strengths and limitations of this study: This is the first study to review how community-based education is currently provided throughout Medical Schools in the UK. The use of Rossi, Lipsey and Freeman’s method of programme evaluation means that the literature was analysed i

Late onset Alzheimer’s disease (LOAD) is the commonest form of dementia, affecting approximately 850,000 patients in the UK alone, predicted to exceed one million by 2025. The cause of LOAD is complex, but several large Genome Wide Association Studies have highlighted 21 genetic loci associated with this devastating disease and the ATP-Binding Cassette Protein, family A, member 7 (ABCA7) is one of these genetic loci. However, the exact reasons behind this association are still unknown, focusing work on identifying functional, pathogenic mutations within this locus. A total of 240 exonic variations within ABCA7 were therefore annotated in order to identify ones potentially altering the functionality of ABCA7. A total of five variants were predicted to be damaging by in silico annotation tools: rs3752233; rs59851484; rs3752237; rs114782266 and a novel mutation at genomic position 19:1056958. These were genotyped in the ARUK DNA Bank resource and three (rs59851484, rs3752239 and 19:1056958) showed tentative association with LOAD. However, lack of power in this study prevented any definitive associations from being formed. A further two variants were examined within functional cell assays. rs881768 had been predicted to affect the splicing of the ABCA7 protein and appeared to do so within minigene cellular assays. However, this did not appear to be the case when RNA from brain tissue harbouring this variation was examined. rs2020000 was examined through the dual luciferase assays, with the minor allele seeming to down regulate the reporter protein by approximately 30% (p<0.02) in these in vitro assays. Functional variations within the ABCA7 locus do play a role in LOAD risk and improvements within functional databases and annotation programmes will assist in identifying these causative mutations, in order to put a halt to LOAD, as well as other destructive complex disorders.

Late onset Alzheimer’s disease (LOAD) is the commonest form of dementia, affecting approximately 850,000 patients in the UK alone, predicted to exceed one million by 2025. The cause of LOAD is complex, but several large Genome Wide Association Studies have highlighted 21 genetic loci associated with this devastating disease and the ATP-Binding Cassette Protein, family A, member 7 (ABCA7) is one of these genetic loci. However, the exact reasons behind this association are still unknown, focusing work on identifying functional, pathogenic mutations within this locus. A total of 240 exonic variations within ABCA7 were therefore annotated in order to identify ones potentially altering the functionality of ABCA7. A total of five variants were predicted to be damaging by in silico annotation tools: rs3752233; rs59851484; rs3752237; rs114782266 and a novel mutation at genomic position 19:1056958. These were genotyped in the ARUK DNA Bank resource and three (rs59851484, rs3752239 and 19:1056958) showed tentative association with LOAD. However, lack of power in this study prevented any definitive associations from being formed. A further two variants were examined within functional cell assays. rs881768 had been predicted to affect the splicing of the ABCA7 protein and appeared to do so within minigene cellular assays. However, this did not appear to be the case when RNA from brain tissue harbouring this variation was examined. rs2020000 was examined through the dual luciferase assays, with the minor allele seeming to down regulate the reporter protein by approximately 30% (p<0.02) in these in vitro assays. Functional variations within the ABCA7 locus do play a role in LOAD risk and improvements within functional databases and annotation programmes will assist in identifying these causative mutations, in order to put a halt to LOAD, as well as other destructive complex disorders.